WO2019131922A1 - Composé aryloxy - Google Patents

Composé aryloxy Download PDF

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Publication number
WO2019131922A1
WO2019131922A1 PCT/JP2018/048284 JP2018048284W WO2019131922A1 WO 2019131922 A1 WO2019131922 A1 WO 2019131922A1 JP 2018048284 W JP2018048284 W JP 2018048284W WO 2019131922 A1 WO2019131922 A1 WO 2019131922A1
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Prior art keywords
group
compound
amino
lower alkyl
methyl
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PCT/JP2018/048284
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English (en)
Japanese (ja)
Inventor
啓太 永井
梨恵 田村
達矢 荻原
淳一朗 小原
賢 安川
綾子 泉田
藤川　徹
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佐藤製薬株式会社
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Publication of WO2019131922A1 publication Critical patent/WO2019131922A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to aryloxy compounds. More specifically, the present invention relates to an aryloxy compound useful for the prevention or treatment of a disease involving intraocular pressure such as glaucoma, and a pharmaceutical composition containing the compound.
  • Glaucoma is an irreversible eye disease characterized by damage to the optic nerve, resulting in damage to visual function such as visual field loss and visual acuity loss. These visual impairments are known to be associated with sustained high intraocular pressure. Therefore, as a treatment for glaucoma, lowering the intraocular pressure is a sure treatment (Non-patent Document 1). Ocular hypertension is a condition in which there is no visual impairment although it is higher than normal intraocular pressure. Since ocular hypertension can progress to glaucoma by sustained high intraocular pressure, treatment to reduce intraocular pressure may be given.
  • a treatment for lowering the intraocular pressure there are, for example, drug treatment, laser treatment, surgical treatment and the like.
  • Drug therapy for example, sympathomimetics (for example, receptor nonselective stimulants, alpha 2 receptor selectivity stimulants etc.), sympatholytic agents (e.g., ⁇ receptor blockers, .alpha..beta receptor blockers and alpha 1) Receptor selective blockers, etc., drugs such as parasympathomimetics, prostaglandin related drugs, carbonic anhydrase inhibitors and Rho kinase (ROCK) inhibitors are used.
  • prostaglandin related drugs are widely used as the first choice drugs because of their excellent intraocular pressure lowering effect.
  • prostaglandin-related drugs are effective for many glaucomatous and hypertensive patients, there are patients who do not show an effect or have an insufficient effect. Furthermore, long-term use may be inappropriate because of side effects. In such cases, a change in the mechanism of action to a different drug is made.
  • Such agents include, for example, beta receptor blockers and carbonic anhydrase inhibitors.
  • the beta receptor adrenergic beta 2 receptor
  • an agonist such as adrenaline
  • Beta receptor blockers suppress aqueous humor production by antagonizing adrenergic beta receptors expressed in the ciliary body of the eye, mainly adrenergic beta 2 receptors, thereby abolishing or diminishing their function, It is known to lower the intraocular pressure.
  • an agent for example, timolol, carteolol and the like are known.
  • Carbonic anhydrase inhibitors retard the formation of bicarbonate ions by blocking carbonic anhydrase II (CA-II) expressed in the ciliary processes of the eye and reduce the subsequent transport of sodium and secretions Thereby suppressing aqueous humor production.
  • CA-II carbonic anhydrase II
  • it is known to lower intraocular pressure and examples of such agents include dorzolamide, brinzolamide, acetazolamide and the like.
  • combination therapy using two or more drugs with different mechanisms of action is also performed.
  • patients often instill a combination of two or more agents, respectively.
  • each drug needs to be instilled at intervals to be applied.
  • drugs that are effective for twice-daily administration depending on the drug and drugs that are effective for three-day administration. This is inconvenient for the patient.
  • a drug for combination therapy a single preparation containing two drugs having different mechanisms of action, that is, a combination eye drop (hereinafter referred to as "combination drug") is known.
  • the combination drug has overcome the above-mentioned problems and is a drug that is beneficial to the patient.
  • a combination drug for example, a combination drug containing a prostaglandin related drug and a ⁇ blocker, a combination drug containing a ⁇ receptor blocker and a carbonic anhydrase inhibitor and the like are known.
  • a combination containing a beta receptor blocker and a carbonic anhydrase inhibitor for example, a combination containing timolol and dorzolamide (patent document 1), a combination containing timolol and brinzolamide (patent document 2), etc. is there.
  • Non-Patent Document 2 describes that timolol, which is a ⁇ -blocker, exhibits different corneal permeability depending on the difference in pH of the preparation and the difference in additives.
  • the stability of the compounds also varies with the formulation. Since the combination preparation combines two compounds having different physical properties into a single formulation, it is difficult to achieve a formulation optimized for each of the two compounds.
  • Patent Document 3 discloses a compound of the following general formula as an active substance in a pharmaceutical preparation for the treatment of obesity and / or diabetes.
  • Patent Document 4 a compound of the following general formula have been disclosed as beta 3 adrenergic agonist.
  • Patent Document 5 a compound of the following general formula have been disclosed as beta 3 adrenergic agonist.
  • Patent Document 6 a compound of the following general formula have been disclosed as beta 3 adrenergic agonist.
  • Patent Document 7 compounds of the following general formula have been disclosed as beta 3 adrenergic agonist.
  • Non-Patent Document 3 discloses, for example, a compound having the following formula as a compound having a prostaglandin F receptor (FP) agonist activity and a carbonic anhydrase inhibitory activity.
  • FP prostaglandin F receptor
  • Non-Patent Document 4 discloses, for example, a compound of the following formula as a compound having an antioxidant activity.
  • the present inventors extensively synthesized and studied aryloxy compounds in order to solve the above problems, and as a result, the compounds represented by the general formula (I) described later exhibited excellent adrenergic beta 2 receptor antagonist activity and carbonic acid carbonate activity. It discovered that it had dehydrating enzyme inhibitory activity, and completed the present invention. That is, the present invention relates to the following compounds [1] to [22].
  • A represents a phenyl group or a 5- or 6-membered ring heteroaryl group (wherein the phenyl group or the 5- or 6-membered ring heteroaryl group is a ⁇ substituent group L> described later or a general formula: -QR 3 And may be substituted by 1 to 3 substituents selected from groups represented by here, Q represents a single bond, a lower alkylene group, a lower alkenylene group or a lower alkynylene group (one or more methylene groups constituting the lower alkylene group are each independently an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a thiocarbonyl group or the general formula: -N (R N) - group represented by (R N represents a hydrogen atom or a lower alkyl group) may be the entire methylene group is replaced by And /
  • [2] B is General formula: (Wherein, R b1 and R b2 are as defined above), a group represented by General formula: (Wherein, R b1 and R b2 are as defined above), a group represented by Or General formula: The compound according to the above [1] or a pharmaceutically acceptable salt thereof, which is a group represented by (wherein R b1 is as defined above). [3] The compound according to the above [1] or [2], wherein R b1 is a halogen atom, a carbamoyl group, a mono-lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, or a pyrazolyl group substituted with a lower alkyl group.
  • A is a general formula: (In each formula, R a1 is a substituent selected from ⁇ Substituent group L> or a group represented by the general formula: -QR 3 ; R a2 and R a3 are each independently a hydrogen atom or a substituent selected from ⁇ substituent group L>.
  • A is a general formula: The compound according to the above [4] or a pharmaceutically acceptable salt thereof, wherein (wherein, R a1 , R a2 and R a3 are as defined above).
  • A is a general formula: The compound according to the above [4] or a pharmaceutically acceptable salt thereof, wherein (wherein, R a1 and R a2 are as defined above).
  • R a1 and R a2 are as defined above.
  • R a1 is a substituent selected from ⁇ Substituent group L>.
  • R a1 is a halogen atom, a nitro group, a cyano group, an amino group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl Group, lower alkanoyl group, di-lower alkylamino group, cyclic amino group, mono-lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, halo-lower alkoxy lower alkyl group, di-lower alkylsulfamoyl group or lower alkoxy lower alkylcoxy group.
  • R 3 is a phenyl group, a furyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, which may be substituted by 1 to 3 substituents selected from ⁇ substituent group M>; Triazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, 1,3,4-thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, morpholino group, thiomorpholino group, 1,4- Oxazepan-4-yl group, 2-oxopyrrolidin-1-yl group, 2-oxooxazolidin-3-yl group, 2-oxopiperidin-1-yl group, 3-oxomorpholino group, 1,1-dioxide thio A morpholino group, 2-oxoazepan-1-yl group, 5-oxo group
  • [12] A has the general formula: The compound according to the above [4] or a pharmaceutically acceptable salt thereof, wherein (wherein, R a1 , R a2 and R a3 are as defined above).
  • [13] A has the general formula: The compound according to the above [12] or a pharmaceutically acceptable salt thereof, wherein (wherein, R a1 and R a2 are as defined above).
  • a nitrogen-containing saturated heterocyclic group in which R 3 is bonded to Q via a ring-constituting nitrogen atom is The compound or the pharmaceutically acceptable salt thereof according to the above [16], which is optionally substituted by 1 to 3 substituents selected from [18]
  • R a2 is a substituent selected from a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group, or a hydroxy lower alkyl group ]
  • the compound or its pharmaceutically acceptable salt as described in any one of-[17].
  • A has the general formula: The compound according to [4] or a pharmaceutically acceptable salt thereof, wherein (wherein, R a1 is as defined above).
  • R a1 is a halogen atom, lower alkyl group, cycloalkyl group, lower alkylamino group, di-lower alkylamino group, cyclic amino group, or phenyl group Acceptable salt.
  • Formula (I) has the following formula (I-2): (Wherein A, R 1 , R 2 and B are as defined above), the compound according to any one of the above [1] to [21] or a pharmaceutically acceptable compound thereof salt.
  • the compound represented by the above-mentioned formula (I) includes not only a racemate of the compound but also all enantiomers and diastereomers which can exist.
  • the present invention also relates to an intraocular pressure selected from the group consisting of glaucoma, hypertonia, elevated intraocular pressure due to trauma, elevated intraocular pressure due to inflammation, increased intraocular pressure due to drugs and postoperative intraocular pressure in mammals (especially humans).
  • a method for the prophylaxis or treatment of a disease involving the administration which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition containing the compound or an intraocular pressure-lowering agent On how to do it.
  • the invention further relates to pharmaceutical compositions and agents for reducing intraocular pressure comprising the compounds of formula (I) as active ingredients.
  • the pharmaceutical composition and the intraocular pressure lowering agent are selected from the group consisting of glaucoma, ocular hypertension, elevated intraocular pressure due to trauma, elevated intraocular pressure due to inflammation, elevated intraocular pressure due to drugs and elevated intraocular pressure after surgery It is used for the prevention or treatment of a disease in which
  • the compounds of the present invention can reduce intraocular pressure because they have an adrenergic beta 2 receptor antagonist activity and a carbonic anhydrase inhibitory activity, as shown in the following examples. Therefore, the present invention is useful as a therapeutic or preventive agent for pathological conditions such as glaucoma and ocular hypertension and the like in which intraocular pressure is involved.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the “lower alkyl group” in the above formula (I) means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group, Isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, isoamyl group, neopentyl group, 1,1-dimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group Hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 , 3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbuty
  • cycloalkyl group in the above formula (I) means a 3- to 8-membered aliphatic cyclic group, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and cyclooctyl group. Etc.
  • halo lower alkyl group in the above-mentioned formula (I) is the above “lower alkyl group” substituted with any one or more, preferably 1 to 5 identical or different said halogen atoms which can be substituted.
  • fluoromethyl group difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 1,2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, chloromethyl And 2-chloroethyl group, 1,2-dichloroethyl group, 2,2,2-trichloroethyl group, bromomethyl group and iodomethyl group.
  • the "lower alkoxy group” in the above formula (I) means a group in which a hydrogen atom of a hydroxyl group is substituted by the above “lower alkyl group”, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and butoxy. And sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy and isohexyloxy groups.
  • halo lower alkoxy group in the above-mentioned formula (I) is the above “lower alkoxy group” substituted with any one or more, preferably 1 to 3 identical or different said halogen atoms which can be substituted.
  • hydroxy lower alkyl group in the above formula (I) means the above “lower alkyl group” substituted at any substitutable position with one or more, preferably one or two hydroxyl groups, Hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, 2-hydroxy-1-methylethyl group, 1-hydroxy-1-methylethyl group, 1, Examples thereof include 2-dihydroxyethyl group and 3-hydroxypropyl group.
  • lower alkoxy lower alkyl group in the above-mentioned formula (I) has the above-mentioned “lower alkoxy group” substituted with one or more, preferably one or two identical or different above-mentioned “lower alkoxy group” of substitutable positions.
  • Lower alkyl group is meant, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 1-methoxy-1-methylethyl, 1,2-dimethoxyethyl and 3-methoxy A propyl group etc. are mentioned.
  • the "lower alkoxycarbonyl group” in the above formula (I) means a group in which the "lower alkoxy group” is bonded to a carbonyl group, that is, an alkoxycarbonyl group having 2 to 7 carbon atoms, for example, a methoxycarbonyl group And ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group and the like.
  • the “lower alkanoyl group” in the above formula (I) means a group in which the lower alkyl group is combined with a carbonyl group, ie, an alkanoyl group having 2 to 7 carbon atoms, and examples thereof include an acetyl group, a propionyl group and a butyryl group, Examples thereof include isobutyryl group, valeryl group, isovaleryl group and pivaloyl group.
  • the “lower alkylthio group” in the above formula (I) means a group in which the above “lower alkyl group” and a sulfur atom are bonded, that is, an alkylthio group having 1 to 6 carbon atoms, such as methylthio group and ethylthio group, Examples thereof include a propylthio group, an isopropylthio group, a butylthio group, a sec-butylthio group, an isobutylthio group, a tert-butylthio group, a pentylthio group, an isopentylthio group, a hexylthio group and an isohexylthio group.
  • the “lower alkylsulfonyl group” in the above formula (I) means a group in which the “lower alkyl group” is bonded to a sulfonyl group, such as a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, isopropanesulfonyl Groups, butanesulfonyl group, sec-butanesulfonyl group, isobutanesulfonyl group, tert-butanesulfonyl group, pentanesulfonyl group, isopentanesulfonyl group, hexanesulfonyl group, isohexanesulfonyl group and the like.
  • a sulfonyl group such as a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group,
  • the “lower alkylamino group” in the above formula (I) means an amino group N-mono-substituted by the above “lower alkyl group", such as N-methylamino group, N-ethylamino group, N- A propylamino group, an N-isopropylamino group, an N-butylamino group, an N-sec-butylamino group, an N-tert-butylamino group and the like can be mentioned.
  • the “di-lower alkylamino group” in the above-mentioned formula (I) means an amino group which is N, N-disubstituted by the same or different “lower alkyl group”, for example, N, N-dimethylamino group, N, N-diethylamino, N, N-dipropylamino, N, N-diisopropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino and N-methyl-N- An isopropylamino group etc. are mentioned.
  • the “cyclic amino group” in the above formula (I) is a 4- to 7-membered saturated member which may contain 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom or sulfur atom in the ring.
  • a cyclic amine such as azetidin-1-yl group, pyrrolidin-1-yl group, piperidin-1-yl group, piperazin-1-yl group, morpholino group, thiomorpholino group, azepan-1-yl group, Examples include 1,4-oxazepan-4-yl and diazepan-1-yl.
  • the "mono lower alkyl carbamoyl group" in the above formula (I) means a group in which the above "lower alkyl group” is N-mono substituted at the nitrogen atom of the carbamoyl group, N-methylcarbamoyl group, N-ethylcarbamoyl group Groups, N-propylcarbamoyl group, N-isopropylcarbamoyl group, N-butylcarbamoyl group, N-sec-butylcarbamoyl group, N-tert-butylcarbamoyl group and the like.
  • the “di-lower alkylcarbamoyl group” in the above formula (I) means a group in which the above “lower alkyl group” is the same as or different from the nitrogen atom of the carbamoyl group is N, N-disubstituted, and N, N-dimethyl Carbamoyl group, N, N-diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, N, N-dipropylcarbamoyl group, N-methyl-N-propylcarbamoyl group, N-methyl-N-tert-butylcarbamoyl group Groups, N-ethyl-N-tert-butylcarbamoyl group, N, N-diisopropylcarbamoyl group and the like.
  • a 5- to 8-membered single member formed by combining a nitrogen atom constituting a carbamoyl group and the same or different “lower alkyl group” bonded to the nitrogen atom.
  • a ring (wherein one or more methylene groups constituting the 5- to 8-membered single ring may be each independently substituted with an oxygen atom in the entire methylene group), or the single ring and It also includes a dicycle formed by condensation with a benzene ring or a pyridine ring, and examples thereof include groups represented by the following formulae.
  • the “lower alkanoylamino group” in the above formula (I) means a group in which the above “lower alkanoyl group” and an amino group or the above “lower alkylamino group” are bonded, and examples thereof include N-acetylamino group, N -Propanoylamino group, N-butanoylamino group, N-pentanoylamino group, N-pivaloylamino group, N-methyl-N-acetylamino group, N-methyl-N-propanoylamino group, N-methyl- N-butanoylamino group, N-methyl-N-pentanoylamino group, N-ethyl-N-acetylamino group, N-ethyl-N-propanoylamino group, N-ethyl-N-butanoylamino group and N-ethyl-N-pentanoylamino group etc.
  • the “lower alkylsulfonylamino group” in the above-mentioned formula (I) means a group in which the above “lower alkylsulfonyl group” and an amino group or the above “lower alkylamino group” are bonded, for example, a methanesulfonylamino group, Ethanesulfonylamino group, propanesulfonylamino group, isopropanesulfonylamino group, butanesulfonylamino group, sec-butanesulfonylamino group, tert-butanesulfonylamino group, N-methyl-methanesulfonylamino group, N-methyl-ethanesulfonyl group Amino group, N-methyl-propanesulfonylamino group, N-methyl-isopropanesulfonylamino group, N-methyl-butanesulfonylamino
  • the “lower alkoxycarbonylamino group” in the above formula (I) means an amino group or a group in which the above “lower alkoxycarbonyl group” is bonded to an amino group or the above “lower alkylamino group”, such as methoxycarbonylamino group, Ethoxycarbonylamino group, propoxycarbonylamino group, isopropoxycarbonylamino group, butoxycarbonylamino group, isobutoxycarbonylamino group, sec-butoxycarbonylamino group, tert-butoxycarbonylamino group, pentyloxycarbonylamino group, neopentyloxy Examples thereof include a carbonylamino group, a hexyloxycarbonylamino group, an isohexyloxycarbonylamino group, an N-methyl-methoxycarbonylamino group, and an N-methyl-ethoxycarbonylamino group.
  • amino lower alkyl group in the above formula (I) means the above “lower alkyl group” substituted at any substitutable position with one or more, preferably one or two amino groups, For example, aminomethyl group, 1-aminoethyl group, 1-aminopropyl group, 2-aminoethyl group, 2-aminopropyl group, 2-amino-1-methylethyl group, 1-amino-1-methylethyl group, 1 And 2-diaminoethyl group and 3-aminopropyl group.
  • lower alkylamino lower alkyl group in the above-mentioned formula (I) is substituted by one or more, preferably one or two, identical or different above-mentioned “lower alkylamino group” at any substitutable position.
  • lower alkyl group means, for example, (methylamino) methyl group, 2- (methylamino) ethyl group, 3- (methylamino) propyl group, 4- (methylamino) butyl group, 5- (methylamino) ) Pentyl group, 6- (methylamino) hexyl group, (ethylamino) methyl group, 2- (ethylamino) ethyl group, (propylamino) methyl group, (isopropylamino) methyl group and 2- (ethylamino) ethyl group And the like.
  • the “di-lower alkylamino lower alkyl group” in the above-mentioned formula (I) is substituted by one or more, preferably one or two identical or different the above-mentioned “di-lower alkylamino groups” at any substitutable position.
  • halo lower alkoxy lower alkyl group in the above-mentioned formula (I) is substituted by one or more, preferably 1 or 2 identical or different above-mentioned “halo lower alkoxy group” at any substitutable position.
  • the above “lower alkyl group” means, for example, fluoromethoxymethyl group, chloromethoxymethyl group, bromomethoxymethyl group, difluoromethoxymethyl group, trifluoromethoxymethyl group, 2- (fluoromethoxy) ethyl group, 2- (chloro) Methoxy) ethyl group, 2- (bromomethoxy) ethyl group, 2- (difluoromethoxy) ethyl group, 2- (trifluoromethoxy) ethyl group, 3- (fluoromethoxy) propyl group, 3- (chloromethoxy) propyl group , 3- (bromomethoxy) propyl, 3- (difluoromethoxy) propyl and 3- (
  • the “di-lower alkyl sulfamoyl group” in the above-mentioned formula (I) means a sulfamoyl group in which two hydrogen atoms of the sulfamoyl group are substituted with the same or different “lower alkyl group”, specifically For example, N, N-dimethylsulfamoyl group, N, N-diethylsulfamoyl group, N-ethyl-N-methylsulfamoyl group, N, N-dipropylsulfamoyl group and the like can be mentioned.
  • lower alkoxy lower alkoxy group in the above-mentioned formula (I) has the above-mentioned “lower alkoxy group” substituted with one or more, preferably one or two identical or different above-mentioned “lower alkoxy group” of substitutable positions.
  • lower alkoxy group means, for example, methoxymethoxy group, 2-methoxyethoxy group, 2-ethoxyethoxy group, 3-methoxypropoxy group, 4-methoxybutoxy group and the like.
  • the “5 or 6-membered ring heteroaryl group” in the above formula (I) is preferably one or more selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom in addition to carbon atoms.
  • the "lower alkylene group" in the above formula (I) means a linear or branched alkylene group having 1 to 6 carbon atoms, and examples thereof include a methylene group, 1-methylmethylene group and 1,1-dimethylmethylene group.
  • Ethylene 1-methylethylene, 1-ethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1,1-diethylethylene, 1,2-diethylethylene, 1- Ethyl-2-methylethylene group, propylene group, 1-methylpropylene group, 2-methylpropylene group, 1,1-dimethylpropylene group, 1,2-dimethylpropylene group, 2,2-dimethylpropylene group, 1-ethyl Propylene group, 2-ethylpropylene group, 2-ethyl-2-methylpropylene group, butylene group, 1-methylbutylene group, 2-methylbutylene group, 1, 1 Dimethyl butylene, 1,2-dimethyl butylene, 2,2-dimethyl butylene group, and pentylene group and hexalene group.
  • the “lower alkenylene group” in the above formula (I) means a linear or branched alkenylene group having 2 to 6 carbon atoms, and examples thereof include vinylene group, 1-methylethenylene group, 1-ethylethenylene group, 1 , 2-Dimethylethenylene, 1,2-Diethylethenylene, 1-ethyl-2-methylethenylene, propenylene, 1-methyl-2-propenylene, 2-methyl-2-propenylene, 1 1,1-dimethyl-2-propenylene group, 1,2-dimethyl-2-propenylene group, 1-ethyl-2-propenylene group, 2-ethyl-2-propenylene group, 1-butenylene group, 2-butenylene group, 1 -Methyl-2-butenylene group, 2-methyl-2-butenylene group, 1,1-dimethyl-2-butenylene group, 1,2-dimethyl-2-butenylene group and the like can be mentioned
  • the “lower alkynylene group” in the above formula (I) means a linear or branched alkynylene group having 2 to 6 carbon atoms, and examples thereof include an ethynylene group and a propynylene group.
  • the “saturated heterocyclic group” relating to the “nitrogen-containing saturated heterocyclic group” in the above formula (I) is one or more hetero atoms selected identical or different from the group consisting of oxygen atom, nitrogen atom and sulfur atom
  • a 3 to 8 membered monocyclic saturated heterocyclic ring such as aziridinyl, azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, Piperazinyl group, morpholino group, thiomorpholino group, azepanyl group, diazepanyl group, oxazepanyl group and the like can be mentioned.
  • the “nitrogen-containing saturated heterocyclic group” in the above formula (I) means a 3- to 8-membered monocyclic “saturated heterocyclic group” having at least one nitrogen atom as a ring-constituting atom, For example, aziridinyl group, azetidinyl group, pyrrolidinyl group, oxazolidinyl group, thiazolidinyl group, piperidinyl group, piperazinyl group, morpholino group, thiomorpholino group, azepanyl group, diazepanyl group, oxazepanyl group and the like can be mentioned.
  • a saturated heterocyclic group is also included, such as 2-oxopyrrolidinyl group, 2-oxooxazolidinyl group, 2-oxopiperidinyl group, 3-oxomorpholino group, 1,1-dioxide thiomorpholino group, Examples thereof include 2-oxoazepanyl group, 5-oxo-1,4-oxazepanyl group, 1 ⁇ 6 , 2-thiazolidine-1,1-dione-2-yl group and the like.
  • the “nitrogen-containing saturated heterocyclic group bonded to Q via a ring-constituting nitrogen atom” in the above-mentioned formula (I) means the above “nitrogen-containing saturated heterocyclic group bonded to Q via a nitrogen atom constituting a ring”
  • “optionally substitutable position” is a substitutable hydrogen atom on a carbon atom, a nitrogen atom, an oxygen atom and / or a sulfur atom, and the substitution of the hydrogen atom is chemically permissible. Mean the site of what results in a stable compound.
  • A represents a phenyl group or a 5- or 6-membered ring heteroaryl group.
  • the phenyl group or the 5- or 6-membered ring heteroaryl group is substituted by 1 to 3 substituents selected from ⁇ substituent group L> or a group represented by the general formula: -QR 3 It may be done.
  • phenyl group of A or a 5- or 6-membered ring heteroaryl group For example, phenyl group, pyrrolyl group, furyl group, thienyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, tetrazolyl group, 1,2,3-oxadiazolyl group, 1,2 2,4-oxadiazolyl group 1,3,4-oxadiazolyl group 1,2,5-oxadiazolyl group 1,2,3-thiadiazolyl group 1,2,4-thiadiazolyl group 1,3,4-thiadiazolyl group And 1,2,5-thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, 1,2,4-triazinyl group, 1,3,5-triazinyl
  • the phenyl group which may be substituted by 1 to 3 substituents or the 5- or 6-membered heteroaryl group of A is preferably, for example, a group represented by the following formula.
  • the phenyl group or 5- or 6-membered ring heteroaryl group which may be substituted by 1 to 3 substituents of A is more preferably, for example, a group represented by the following formula.
  • the phenyl group or 5- or 6-membered ring heteroaryl group which may be substituted by 1 to 3 substituents of A is particularly preferably, for example, a group represented by the following formula.
  • R a1 is a substituent selected from ⁇ Substituent group L> or a group represented by the general formula: -QR 3 ;
  • R a2 and R a3 are each independently a hydrogen atom or a substituent selected from ⁇ substituent group L>.
  • ⁇ substituent group L> is Halogen atom, hydroxyl group, nitro group, cyano group, amino group, lower alkyl group, cycloalkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, hydroxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxy carbonyl Group, lower alkanoyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkylamino group, di-lower alkylamino group, cyclic amino group, carbamoyl group, mono-lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, lower alkanoylamino group, It is a group consisting of a lower alkylsulfonylamino group, a lower alkoxycarbonylamino group, a halo lower alkoxy lower alkyl group, a di
  • the substituent selected from ⁇ Substituent group L> is preferably a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group, a hydroxy lower group.
  • Alkyl group lower alkoxy lower alkyl group, lower alkoxycarbonyl group, lower alkanoyl group, di lower alkylamino group, cyclic amino group, carbamoyl group, mono lower alkyl carbamoyl group, di lower alkyl carbamoyl group, halo lower alkoxy lower alkyl group, Di lower alkylsulfamoyl group and lower alkoxy lower alkyloxy group are mentioned.
  • the substituent selected from ⁇ substituent group L> of R a1 is preferably a halogen atom, nitro group, cyano group, amino group, lower alkyl group, cycloalkyl group, halo lower alkyl group, lower alkoxy group, hydroxy Lower alkyl group, lower alkoxy lower alkyl group, lower alkoxy carbonyl group, lower alkanoyl group, di lower alkyl amino group, cyclic amino group, mono lower alkyl carbamoyl group, di lower alkyl carbamoyl group, halo lower alkoxy lower alkyl group, di lower Alkyl sulfamoyl group and lower alkoxy lower alkyloxy group are mentioned.
  • Q represents a single bond, a lower alkylene group, a lower alkenylene group or a lower alkynylene group.
  • one or more methylene groups constituting the lower alkylene group are each independently an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a thiocarbonyl group or a general formula: -N (R
  • the entire methylene group may be replaced with a group represented by N 2 ) (wherein R N represents a hydrogen atom or a lower alkyl group), and / or a hydrogen constituting the methylene group is a halogen atom, a cyano group And may be substituted with a hydroxyl group or a lower alkyl group.
  • the lower alkenylene group for Q For example, vinylene, 1-methylethenylene, 1-ethylethenylene, 1,2-dimethylethenylene, 1,2-diethylethenylene, 1-ethyl-2-methylethenylene, propenylene, 1 2-methyl-2-propenylene group, 2-methyl-2-propenylene group, 1,1-dimethyl-2-propenylene group, 1,2-dimethyl-2-propenylene group, 1-ethyl-2-propenylene group, 2- Ethyl-2-propenylene group, 1-butenylene group, 2-butenylene group, 1-methyl-2-butenylene group, 2-methyl-2-butenylene group, 1,1-dimethyl-2-butenylene group or 1,2- And dimethyl-2-butenylene group and the like.
  • a vinylene group is preferable.
  • an ethynylene group, a propynylene group, etc. are mentioned, for example, Especially, an ethynylene group is preferable.
  • One or more methylene groups constituting the lower alkylene group of Q are each independently an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a thiocarbonyl group or a general formula: -N (R N ) - group represented by (R N represents a hydrogen atom or a lower alkyl group) may be the entire methylene group is replaced by, and / or a hydrogen is a halogen atom constituting a methylene group, a cyano group, a hydroxyl group Or may be substituted by a lower alkyl group.
  • a substituted or substituted group for example, a group selected from the following formulas is preferable.
  • Q is more preferably, for example, a single bond, a methylene group, an ethylene group and a group selected from the following formulae.
  • Q may be a single bond or a lower alkylene group.
  • one or more methylene groups constituting the lower alkylene group are each independently substituted with an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group or a thiocarbonyl group as a whole. May be
  • RN is a hydrogen atom or a lower alkyl group.
  • R N is for example a hydrogen atom or a methyl group are preferred, more preferably a hydrogen atom.
  • R 3 represents a phenyl group, a 5- or 6-membered ring heteroaryl group or a nitrogen-containing saturated heterocyclic group bonded to Q via a ring nitrogen atom.
  • the phenyl group, the 5- or 6-membered heteroaryl group, or the saturated heterocyclic group bonded to Q via a ring nitrogen atom is one to three substituents selected from ⁇ Substituent group M>. And may be substituted.
  • phenyl group of R 3 or a 5- or 6-membered ring heteroaryl group For example, phenyl group, pyrrolyl group, furyl group, thienyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, tetrazolyl group, 1,2,3-oxadiazolyl group, 1,2 2,4-oxadiazolyl group 1,3,4-oxadiazolyl group 1,2,5-oxadiazolyl group 1,2,3-thiadiazolyl group 1,2,4-thiadiazolyl group 1,3,4-thiadiazolyl group And 1,2,5-thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, 1,2,4-triazinyl group, 1,3,5-triazinyl group,
  • phenyl pyrazolyl, thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl and , 2,4-triazinyl and the like.
  • ⁇ substituent group M> is Halogen atom, hydroxyl group, nitro group, cyano group, amino group, lower alkyl group, cycloalkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, hydroxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxy carbonyl Group, lower alkanoyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkylamino group, di-lower alkylamino group, cyclic amino group, carbamoyl group, mono-lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, lower alkanoylamino group, And lower alkylsulfonylamino groups and lower alkoxycarbonylamino groups.
  • Preferred examples of the substituent selected from ⁇ Substituent group M> include a halogen atom, a cyano group, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group and a lower alkoxy carbonyl group.
  • R 3 For example, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-iodophenyl group, 3-iodophenyl group, 4-iodophenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 2-methylphenyl group, 3- Methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-propylphenyl, 3-propylphenyl, 4-propylphenyl, 2-trifluoro Phenyl group, 3-trifluorophenyl group, 4-trifluorophenyl group, 2-hydroxy
  • R a2 is a hydrogen atom or a substituent selected from ⁇ Substituent group L>.
  • R a2 for example, a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group and the like are preferable, and a lower alkyl group is more preferable.
  • a fluorine atom, a chlorine atom, a cyano group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a trifluoromethyl group, a methoxy group and the like are preferable, and a methyl group is more preferable.
  • R a3 is a hydrogen atom or a substituent selected from ⁇ Substituent group L>.
  • R a3 for example, a hydrogen atom, a halogen atom, a hydroxyl group or a lower alkyl group is preferable, and a hydrogen atom or a hydroxyl group is more preferable.
  • R 1 and R 2 each independently represent a hydrogen atom or a lower alkyl group.
  • R 1 and R 2 For example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, isoamyl group, neopentyl group, 1,1-dimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl
  • methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like are preferable, and methyl group is more preferable.
  • R 1 and R 2 for example, a hydrogen atom or a methyl group is preferable.
  • X 1 represents a single bond or a lower alkylene group.
  • X 2 is a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a group represented by the general formula: -N (R N )-, a general formula: -N (R N ) CO- A group, a group represented by the general formula: -CON (R N )-, a group represented by the general formula: -N (R N ) SO 2 -or a general formula: -SO 2 N (R N )- .
  • R N represents a hydrogen atom or a lower alkyl group.
  • W 1 represents a nitrogen atom or a methine group
  • W 2 represents an oxygen atom or a sulfur atom
  • W 3 represents a nitrogen atom or a methine group.
  • B is preferably selected from any of the following formulas:
  • R b1 is a substituent selected from ⁇ Substituent group N>, or a phenyl group or a 5- or 6-membered heteroaryl group.
  • the phenyl group or the 5- or 6-membered ring heteroaryl group may be substituted by a lower alkyl group.
  • phenyl group of R b1 or the 5- or 6-membered ring heteroaryl group For example, phenyl group, pyrrolyl group, furyl group, thienyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, tetrazolyl group, 1,2,3-oxadiazolyl group, 1,2 2,4-oxadiazolyl group 1,3,4-oxadiazolyl group 1,2,5-oxadiazolyl group 1,2,3-thiadiazolyl group 1,2,4-thiadiazolyl group 1,3,4-thiadiazolyl group And 1,2,5-thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, 1,2,4-triazinyl group, 1,3,5-triazinyl group
  • ⁇ Substituent group N> is Halogen atom, hydroxyl group, nitro group, cyano group, amino group, lower alkyl group, cycloalkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, hydroxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxy carbonyl Group, lower alkanoyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkylamino group, di-lower alkylamino group, carbamoyl group, mono-lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, amino lower alkyl group, lower alkylamino lower group It is a group consisting of an alkyl group and a di-lower alkylamino lower alkyl group.
  • the substituent selected from ⁇ Substituent group N> is preferably a halogen atom, lower alkoxy lower alkyl group, carbamoyl group, mono lower alkyl carbamoyl group, di lower alkyl carbamoyl group, lower alkyl amino lower alkyl group or di lower And alkylamino lower alkyl groups and the like.
  • a halogen atom, a carbamoyl group, a mono lower alkyl carbamoyl group, a di lower alkyl carbamoyl group and the like are more preferable.
  • the “phenyl group or 5- or 6-membered ring heteroaryl group which may be substituted with lower alkyl group” of R b1 is an unsubstituted phenyl group, an unsubstituted 5- or 6-membered ring heteroaryl group, lower alkyl
  • a phenyl group substituted by a group or a 5- or 6-membered heteroaryl group substituted by a lower alkyl group For example, phenyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group, 1-imidazolyl group, 2-imidazolyl group, 4-Imidazolyl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl, 3-methyl-1H -Pyrazol-5-yl group, 4-
  • 1H-pyrazol-1-yl group, 1H-pyrazol-3-yl group, 1H-pyrazol-4-yl group, 1-methyl-1H-pyrazol-5-yl group, 3-methyl-1H-pyrazole- 5-yl group, 4-methyl-1H-pyrazol-5-yl group, 4-methyl-1H-pyrazol-3-yl group, 1-methyl-1H-pyrazol-4-yl group, 5-methyl-1H- Pyrazol-4-yl group, 1-ethyl-1H-pyrazol-5-yl group, 1-propyl-1H-pyrazol-5-yl group, 1-isopropyl-1H-pyrazol-5-yl group, 1-ethyl- 1H-pyrazol-4-yl group, 1-propyl-1H-pyrazol-4-yl group, 1-isopropyl-1H-pyrazol-4-yl group and the like are preferable, Particularly preferred are 1-ethyl-1H-pyrazol-5-yl group and
  • R b1 are For example, fluorine atom, chlorine atom, bromine atom, iodine atom, methoxymethyl group, ethoxymethyl group, carbamoyl group, N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, N-isopropylcarbamoyl group, amino Methyl group, (methylamino) methyl group, (ethylamino) methyl group, (propylamino) methyl group, (isopropylamino) methyl group, (dimethylamino) methyl group, 1H-pyrazol-1-yl group, 1H-pyrazole -3-yl group, 1H-pyrazol-4-yl group, 1-methyl-1H-pyrazol-5-yl group, 3-methyl-1H-pyrazol-5-yl group, 4-methyl-1H-pyrazole-5 -Yl group, 4-
  • R b2 is a hydrogen atom or a halogen atom.
  • halogen atom of R b2 examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a fluorine atom and a chlorine atom are preferable.
  • the compounds of the invention may have asymmetric centers, chiral axes, and chiral surfaces.
  • the compounds of the invention may occur as racemates, as racemic mixtures and as individual diastereomers. Also, all optical isomers and their mixtures are included in the present invention. Additionally, the compounds disclosed herein may exist as tautomers, and even if only one tautomeric structure is drawn, both tautomeric forms are within the scope of the present invention. It is intended to be conjugated by
  • the invention also includes within its scope the N-oxides of the compounds of formula (I) above.
  • N-oxides can be formed on any available nitrogen atom.
  • N-oxides may be formed by conventional means, for example by reacting a compound of formula (I) with oxone in the presence of wet alumina.
  • the compounds of the present invention also encompass so-called labeling compounds in which some or all of the atoms constituting the compound represented by formula (I) are substituted by their isotopes.
  • isotopes used for labeling include, but are not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 32 P, 35 S, 36 Cl, 123 I, 125 I and the like can be suitably used.
  • These labeled compounds can be prepared by the methods disclosed herein by replacing non-isotopically labeled reagents with corresponding isotopically labeled reagents, or by any suitable method.
  • the "pharmaceutically acceptable salt” of the compound of the present invention means a pharmaceutically acceptable conventional one.
  • an acidic heteroaryl group such as a carboxyl group, a hydroxyl group or a tetrazolyl group
  • the base addition salt in the carboxyl group, hydroxyl group or acidic heteroaryl group, or the amino group in the case of having an amino group or a basic heteroaryl group Mention may be made of the salts of acid addition salts in groups or in basic heteroaryl groups.
  • the base addition salt examples include inorganic salts such as aluminum salt, calcium salt, lithium salt, magnesium salt, potassium salt, sodium salt and zinc salt; for example, arginine salt, benzathine salt, chloroprocaine salt, choline salt, diethanolamine salt, Organic amine salts such as ethanolamine salt, ethylenediamine salt, histidine salt, lysine salt, meglumine salt, procaine salt and the like can be mentioned.
  • the acid addition salt examples include hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogensulfate, borate, nitrate, phosphate, hydrogenphosphate, dihydrogenphosphate
  • Inorganic salts such as hexafluorophosphate, perchlorate, bicarbonate, carbonate, formate, etc .
  • Organic acid salts such as salts, oxolates, palmitates, pamoates, sugars, stearates, etc .
  • the methods for producing pharmaceutically acceptable salts of the compounds according to the present invention can be carried out by appropriately combining methods commonly used in the field of synthetic organic chemistry. Specifically, neutralization titration of a free solution of the compound according to the present invention with an alkaline solution or an acidic solution may, for example, be mentioned.
  • the "pharmaceutically acceptable salts" of the present invention also include solvates with water or pharmaceutically acceptable solvents such as ethanol.
  • the method for producing the compound of the present invention is specifically described.
  • the present invention is not limited to these production methods.
  • the order of reactions may be changed as appropriate.
  • the reaction may be performed from a process or site that seems reasonable.
  • a substituent conversion (conversion or further modification of a substituent) step may be inserted appropriately between the steps.
  • protection and deprotection may be appropriately performed.
  • the protective group which can be used in each reaction, and the method of protection / deprotection are not limited as long as they are the protective group used in ordinary organic synthesis and the method of protection / deprotection.
  • Protecting groups which can be used in each reaction, and methods of protection / deprotection are described in, for example, literature methods [Protective Groups in Organic Synthesis, Third Edition, T., et al. W. The method may be appropriately selected and used according to a method according to Greene (T. W. Greene), John Wiley & Sons (1999) or a similar method. The protection / deprotection may be carried out any number of times during any series of processes for producing the compound represented by formula (I), if necessary.
  • the compound (b) may be used as a free amine or as an acid addition salt.
  • the acid addition salt include hydrochloride, sulfate, phosphate, perchlorate, p-toluenesulfonate, benzenesulfonate, methanesulfonate and trifluoroacetate.
  • the amount of compound (b) to be used is generally 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (a).
  • a base may be added as necessary.
  • the base to be used for example, N, N-diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, cesium fluoride, sodium hydride, potassium tert-butoxide, lithium hydroxide, sodium hydroxide or the like
  • potassium hydroxide and the like for example, N, N-diisopropylethylamine, triethylamine and the like are preferable, and for example, N, N-diisopropylethylamine is more preferable.
  • the amount of the base is usually 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (b).
  • the reaction temperature is usually 0 ° C. to 150 ° C., preferably 10 ° C. to 150 ° C., more preferably 20 ° C. to 130 ° C.
  • the reaction time is usually 1 hour to 24 hours, preferably 1 hour to 6 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and, for example, toluene, methanol, ethanol, 1-propanol, 2-propanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl -2-Pyrrolidone, dimethyl sulfoxide, chloroform, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether, ethyl acetate, methyl acetate, propyl acetate, acetonitrile and the like.
  • Preferred is toluene, methanol, ethanol, 1-propanol, 2-propanol or the like, and more preferred is toluene, methanol or ethanol.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • combinations of two or more of the above reaction solvents include combinations of methanol and toluene, combinations of ethanol and toluene, combinations of 1-propanol and toluene, combinations of 2-propanol and toluene, and combinations of methanol, ethanol and toluene And the like, preferably a combination of methanol and toluene, a combination of ethanol and toluene, or a combination of methanol, ethanol and toluene.
  • a commercial item can be used for a compound (1), and you may manufacture it by combining suitably the method according to a well-known method or an Example, or the method according to it as needed.
  • the leaving group LG of the compound (2) is not particularly limited as long as it leaves the compound (1) to form the compound (a), and examples of the leaving group include 2-methyl.
  • a commercial item can be used for a compound (2), and you may manufacture it by combining suitably the method according to a well-known method or an Example, or the method according to it as needed.
  • the compound (2) include, for example, 2-methylbenzenesulfonic acid (S) -glycidyl, 3-methylbenzenesulfonic acid (S) -glycidyl, 4-methylbenzenesulfonic acid (S) -glycidyl, 2-nitrobenzene Sulfonic acid (S) -glycidyl, 3-nitrobenzenesulfonic acid (S) -glycidyl, 4-nitrobenzenesulfonic acid (S) -glycidyl, 2-chlorobenzenesulfonic acid (S) -glycidyl, 3-chlorobenzenesulfonic acid (S)- Glycidyl, 4-Chlorobenzenesulfonic acid (S) -glycidyl, 2-bromobenzenesulfonic acid (S) -glycidyl, 3-bromobenzenesulfonic acid (S) -glycidyl, 4-bromo
  • the amount of compound (2) to be used is generally 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (1).
  • the compound (1) may be used in excess to the compound (2).
  • the amount of compound (1) to be used is generally 1.5 to 5 mol, preferably 2 to 3 mol, per 1 mol of compound (2).
  • the reaction of the above scheme 2 is preferably performed in the presence of a base.
  • a base for example, cesium fluoride, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium hydride, sodium hydride, potassium hydride, lithium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium hydroxide, Examples thereof include sodium hydroxide, potassium hydroxide, N, N-diisopropylethylamine, triethylamine and the like.
  • cesium fluoride and sodium hydride are preferable.
  • the amount of the base is usually 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (1).
  • the reaction temperature is usually 0 ° C. to 120 ° C., preferably 5 ° C. to 100 ° C., more preferably 10 ° C. to 40 ° C.
  • the reaction time is usually 1 hour to 24 hours, preferably 1 hour to 20 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, chloroform, dichloromethane, Tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether, ethyl acetate, methyl acetate, propyl acetate, acetone, acetonitrile and the like can be mentioned, preferably N, N-dimethylformamide And dimethyl sulfoxide.
  • the above-mentioned “protecting group” of P 1 and P 2 represents a protecting group of a nitrogen atom of a sulfonamide group.
  • the protective groups P 1 and P 2 are not particularly limited as long as they have the function, and for example, tert-butyl group; for example, benzyl group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group, 3,4- Aralkyl groups such as dimethoxybenzyl group, 2-nitrobenzyl group, 4-nitrobenzyl group, benzhydryl group and trityl group; for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group or pivaloyl group A lower alkanoyl group such as an arylacyl group such as a benzoyl group or 4-acetoxybenzoyl group; an arylalkanoyl group such as a
  • a commercial item can be used for a compound (3), and you may manufacture it by combining suitably the method according to a well-known method or an Example, or the method according to it as needed.
  • the compound (3) include, for example, 4-bromo-3-fluorobenzenesulfonyl chloride, 4-bromo-3-methylbenzenesulfonyl chloride, 4-bromo-3-chlorobenzenesulfonyl chloride, 4-bromo-3, 5 -Dimethylbenzenesulfonyl chloride, 5-bromo-4-chlorothiophene-2-sulfonyl chloride, 4-bromo-2-fluorobenzenesulfonyl chloride, 4-bromo-2,3-difluorobenzenesulfonyl chloride and 4-bromo-2, 5-difluorobenzenesulfonyl chloride and the like.
  • a commercial item can be used for a compound (4), and you may manufacture it by combining suitably the method according to a well-known method or an Example, or the method according to it as needed.
  • the compound (4) include tert-butylamine, dibenzylamine, bis (4-methoxybenzyl) amine and bis (2,4-dimethoxybenzyl) amine.
  • the amount of compound (4) to be used is generally 1 to 3 mol, preferably 1 to 1.5 mol, per 1 mol of compound (3).
  • the reaction of the above scheme 3 is preferably performed in the presence of a base.
  • a base for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium hydride, sodium hydride, potassium hydride, lithium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium hydroxide, sodium hydroxide, Potassium hydroxide, N, N-diisopropylethylamine, triethylamine, N-methylmorpholine, pyridine and the like can be mentioned, with preference given to N, N-diisopropylethylamine and triethylamine.
  • the amount of the base is usually 1 to 3 mol, preferably 1 to 1.5 mol, per 1 mol of compound (3).
  • the reaction temperature is generally ⁇ 10 ° C. to 40 ° C., preferably 0 ° C. to 30 ° C.
  • the reaction time is usually 1 hour to 48 hours, preferably 1 hour to 24 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, chloroform, dichloromethane, Solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether, ethyl acetate, methyl acetate, propyl acetate and acetonitrile can be mentioned, with preference given to tetrahydrofuran.
  • the carboxylic acid salt of the compound (6) which is a cyanoacetate in the presence of a palladium catalyst (further optionally, a phosphine ligand) is a compound having a halogen atom while decarboxylating (5 Compound (7) can be obtained by coupling with.
  • a commercial item can be used for a compound (6), and you may manufacture it by combining suitably the method according to a well-known method or an Example, or the method according to it as needed.
  • Specific examples of the compound (6) include sodium 2-cyanoacetate, potassium 2-cyanoacetate, sodium 2-cyanopropionate, potassium 2-cyanopropionate, potassium 2-cyano-2-methylpropionate, and the like. Examples thereof include sodium cyano-2-methylpropionate, potassium 2-cyanobutanoate and sodium 2-cyanobutanoate.
  • the amount of compound (6) to be used is generally 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (5).
  • palladium catalysts examples include allylpalladium (II) chloride dimer, tris (dibenzylideneacetone) dipalladium (0) (Pd 2 (dba) 3 ) and bis (triphenylphosphine) palladium (II) dichloride (PPh 3 ) 2 PdCl 2 ) and the like.
  • the amount of palladium catalyst to be used is generally 0.01 to 0.5 mol, preferably 0.05 to 0.2 mol, per 1 mol of compound (5).
  • phosphine ligand for example, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (XantPhos), 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-triisopropyl -1,1'-biphenyl (XPhos), dicyclohexyl (2 ', 6'-dimethoxy- [1,1'-biphenyl] -2-yl) phosphine (SPhos) or 9,9-dimethyl-4,5-bis (Di-tert-butylphosphino) xanthene and the like.
  • XantPhos 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene
  • XantPhos 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-triisopropyl -1,1'-biphenyl
  • the amount of the phosphine ligand to be used is generally 0.01 to 1.5 mol, preferably 0.05 to 0.5 mol, per 1 mol of compound (5).
  • the reaction temperature is usually 0 ° C to 160 ° C, preferably 25 ° C to 150 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 3 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include toluene, xylene, mesitylene, 1,4-dioxane, 1,2-dimethoxyethane, diethylene glycol dimethyl ether and methyl tert-butyl ether. Preferred are xylene, mesitylene and diethylene glycol dimethyl ether.
  • R 1 , R 2 and B are as defined above. Wherein R 1 , R 2 and B are as defined above, P 1 is a protecting group, and P 2 is a protecting group or a hydrogen atom. It is. Can be obtained by removing the P 1 and P 2 protecting groups of the compound represented by the formula (compound (7)). More specifically, compound (8) can be obtained by removing the P 1 and P 2 protecting groups of compound (7) in the presence of an acid (and optionally, anisole or thioanisole). .
  • Examples of the acid to be used include trifluoroacetic acid, hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid and the like, with preference given to trifluoroacetic acid and sulfuric acid.
  • the amount of acid used is usually 0.01 mol to a large excess with respect to 1 mol of compound (7).
  • the amount of anisole or thioanisole to be used is generally 0.01 mol to a large excess with respect to 1 mol of compound (7).
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 20 ° C. to 80 ° C.
  • the reaction time is usually 0.5 hour to 48 hours, preferably 1 hour to 6 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include dichloromethane, 1,2-dichloroethane, chloroform and the like, preferably dichloromethane and chloroform.
  • the reaction may be carried out without a solvent.
  • Formula (9) [In the formula, R 1 , R 2 and B are as defined above.
  • the compound of the formula (compound (9)) is represented by the above formula (8) [wherein R 1 , R 2 and B are as defined above. It can obtain by hydrolyzing the cyano group of the compound (compound (8)) represented by these. More specifically, it can be obtained by hydrolyzing the cyano group of compound (8) in the presence of an acid or a base.
  • Examples of the acid to be used include acetic acid, formic acid, phthalic acid, sulfuric acid and hydrochloric acid, with preference given to sulfuric acid and hydrochloric acid.
  • the amount of the acid used is usually 0.01 mol to a large excess with respect to 1 mol of compound (8).
  • Examples of the base to be used include lithium hydroxide, sodium hydroxide and potassium hydroxide, and the like, with preference given to sodium hydroxide and potassium hydroxide.
  • the amount of the base to be used is generally 0.01 mol to a large excess with respect to 1 mol of compound (8).
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 160 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 16 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, ethylene glycol, water, tetrahydrofuran, Examples thereof include 2-methyltetrahydrofuran, 1,4-dioxane, cyclohexane, 1,3-dimethylbenzene and toluene, with preference given to methanol, ethanol, ethylene glycol and water.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • Examples of a combination of two or more of the above reaction solvents include a combination of methanol and water, a combination of ethanol and water, a combination of ethylene glycol and water, and the like, preferably a combination of ethanol and water.
  • Formula (10) [In the formula, R 1 , R 2 and B are as defined above.
  • the compound of the formula (compound (10)) is represented by the above formula (9) [wherein R 1 , R 2 and B are as defined above.
  • an azidation agent such as diaryl phosphate azide (eg, diphenyl phosphate azide etc.)
  • the amount of the azidation agent to be used is generally 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (9).
  • Examples of the base to be used include triethylamine, N, N-diisopropylethylamine, N-methylpyrrolidine and the like.
  • the amount of the base to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (9).
  • the reaction temperature is generally 0 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 3 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, 1-propanol, 2 And -propanol, tert-butanol, toluene, benzene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, acetone, methyl ethyl ketone, methylene chloride and chloroform, etc. It is 1,4-dioxane.
  • Compound (10) is a compound of compound (9) and halogenated formate (eg, methyl chloroformate) in the presence of the corresponding acid halide (eg, acid chloride, acid bromide, acid iodide, etc.) of compound (9), or a base Alkali metal azide (eg, sodium azide or the like) to a mixed acid anhydride obtained from ethyl chloroformate, ethyl bromoformate, propyl chloroformate, butyl chloroformate, isobutyl chloroformate, isobutyl bromoformate, hexyl chloroformate, etc.) It can also be obtained by reacting an azidation agent such as potassium azide or the like or trialkylsilyl azide (eg, trimethylsilyl azide, triethylsilyl azide, tri tert-butylsilyl azide or the like).
  • an azidation agent such as potassium azide or the
  • the amount of the azidation agent to be used is generally 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (9).
  • the reaction temperature is generally ⁇ 30 ° C. to 100 ° C., preferably ⁇ 20 ° C. to 30 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 3 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, but, for example, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, N, N-dimethylformamide, N, N-dimethyl form
  • Examples include acetamide, N-methyl-2-pyrrolidone, acetone, methyl ethyl ketone, methylene chloride, chloroform, water and the like, with preference given to acetonitrile, tetrahydrofuran, acetone, methylene chloride, chloroform and water.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • Step (8-1) In the step (8-1), the above formula (10) [wherein R 1 , R 2 and B are as defined above].
  • the reaction temperature is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 3 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and includes, for example, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, xylene, water and the like, preferably tetrahydrofuran, 1,4-dioxane And water.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • Step (8-2) In the step (8-2), the above formula (11) wherein R 1 , R 2 and B are as defined above.
  • the compound (compound (11)) represented by the formula] is reacted with a base to give a compound of the formula (b-1): wherein R 1 , R 2 and B are as defined above. ] (Step of obtaining the compound (compound (b-1)))
  • Examples of the base to be used include sodium hydroxide and potassium hydroxide.
  • the amount of the base to be used is generally 1 mol to 20 mol, preferably 1 mol to 10 mol, per 1 mol of the starting compound (10).
  • the reaction temperature is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 3 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and includes, for example, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, xylene, water and the like, preferably tetrahydrofuran, 1,4-dioxane And water.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • a commercial item can be used for a compound (12), and you may manufacture it by combining suitably the method according to a well-known method or an Example, or the method according to it as needed.
  • the compound (12) include, for example, 3-fluoro-4-methylbenzenesulfonyl chloride, 3-chloro-4-methylbenzenesulfonyl chloride, 3-bromo-4-methylbenzenesulfonyl chloride, 3-iodo-4- Methylbenzenesulfonyl chloride, 4-methyl-3-nitrobenzenesulfonyl chloride, 4-methyl-3- (trifluoromethyl) benzenesulfonyl chloride, 3-cyano-4-methylbenzenesulfonyl chloride, 3-acetyl-4-methylbenzenesulfonyl Chloride, 3-acetamido-4-methylbenzenesulfonyl chloride, 3-carbamoyl-4-methylbenzenesulfonyl chloride, methyl 5- (chlorosulfonyl) -2-methylbenzoate, 5- (chlorosulfonyl) -2-methylbenzoate,
  • a commercial item can be used for a compound (4), and you may manufacture it by combining suitably the method according to a well-known method or an Example, or the method according to it as needed.
  • the compound (4) include tert-butylamine, dibenzylamine, bis (4-methoxybenzyl) amine and bis (2,4-dimethoxybenzyl) amine.
  • the amount of compound (4) to be used is generally 1 to 3 mol, preferably 1 to 2.5 mol, per 1 mol of compound (12).
  • the reaction of the above scheme 9 may be carried out in the presence of a base.
  • a base for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium hydride, sodium hydride, potassium hydride, lithium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium hydroxide, sodium hydroxide,
  • Examples thereof include potassium hydroxide, pyridine, N, N-diisopropylethylamine, triethylamine and the like.
  • N, N-diisopropylethylamine and triethylamine are preferable.
  • the amount of the base is usually 1 to 3 mol, preferably 1 to 1.5 mol, more preferably 1 to 1.3 mol, per 1 mol of compound (12).
  • the reaction temperature is generally ⁇ 10 ° C. to 40 ° C., preferably ⁇ 10 ° C. to 30 ° C.
  • the reaction time is usually 30 minutes to 48 hours, preferably 30 minutes to 2 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, chloroform, dichloromethane, Examples include diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether, pyridine, acetone, ethyl acetate, methyl acetate, propyl acetate, acetonitrile and the like, preferably tetrahydrofuran It is.
  • Formula (14) [wherein, B is as defined above, X is a halogen atom, P 1 is a protecting group, and P 2 is a protecting group or a hydrogen atom.
  • X is a halogen atom
  • P 1 is a protecting group
  • P 2 is a protecting group or a hydrogen atom
  • Me is methyl It is a group.
  • compound (14) can be obtained by reacting compound (13) with a halogenating agent (optionally, a radical initiator) such as N-bromosuccinimide or N-chlorosuccinimide.
  • halogenating agent examples include, for example, N-bromosuccinimide (NBS) and N-chlorosuccinimide (NCS), bromine and chlorine.
  • the amount of the halogenating agent to be used is generally 1 to 3 mol, preferably 1 to 2 mol, more preferably 1 to 1.5 mol, per 1 mol of compound (13).
  • radical initiator examples include, for example, 2,2'-azobis (isobutyronitrile) (AIBN), 1,1'-azobis (cyclohexanecarbonitrile) (ABCN), benzoyl peroxide and the like.
  • AIBN 2,2'-azobis (isobutyronitrile)
  • ABCN 1,1'-azobis (cyclohexanecarbonitrile)
  • benzoyl peroxide examples include, for example, 2,2'-azobis (isobutyronitrile) (AIBN), 1,1'-azobis (cyclohexanecarbonitrile) (ABCN), benzoyl peroxide and the like.
  • the amount of the radical initiator to be used is generally 0.01 to 1 mol, preferably 0.05 to 0.5 mol, more preferably 0.1 to 0.3 mol, per 1 mol of compound (13). .
  • the reaction temperature is generally ⁇ 10 ° C. to 100 ° C., preferably 0 ° C. to 90 ° C.
  • the reaction time is usually 1 hour to 48 hours, preferably 1 hour to 6 hours.
  • the reaction solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include acetonitrile, chloroform, carbon tetrachloride, ethyl acetate, propyl acetate, isopropyl acetate, cyclohexane, benzene, chlorobenzene, trifluoromethylbenzene and the like.
  • a commercial item can be used for a compound (15), and you may manufacture it by combining suitably the method according to a well-known method or an Example, or the method according to it as needed.
  • the compound (15) include, for example, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, isovaleronitrile, 2-methylbutyronitrile and the like.
  • the amount of compound (15) to be used is generally 1 to 10 mol, preferably 1 to 5 mol, more preferably 1 to 3 mol, per 1 mol of compound (14).
  • Examples of the base to be used include lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, lithium diisopropylamide, lithium dicyclohexylamide, sodium dicyclohexylamide, lithium cyclohexylisopropylamide and the like, with preference given Is lithium bis (trimethylsilyl) amide or lithium diisopropylamide.
  • the amount of the base is usually 1 to 3 mol, preferably 1 to 1.5 mol, more preferably 1 to 1.2 mol, per 1 mol of compound (15).
  • the reaction temperature is usually ⁇ 78 ° C. to 40 ° C., preferably ⁇ 10 ° C. to 10 ° C.
  • the reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 3 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether, toluene, hexane and cyclohexane Is preferably tetrahydrofuran.
  • Formula (17) [wherein, R 1 , R 2 and B are as defined above, P 1 is a protecting group, and P 2 is a protecting group or a hydrogen atom. Wherein R 1 , R 2 and B are as defined above, P 1 is a protecting group, and P 2 is a protecting group or a hydrogen atom. It is. It can obtain by hydrolysis of the cyano group of the compound (compound (16)) represented by these. More specifically, compound (17) can be obtained by hydrolyzing the cyano group of compound (16) in the presence of an acid or a base.
  • Examples of the acid to be used include acetic acid, formic acid, sulfuric acid, phthalic acid and hydrochloric acid.
  • the amount of the acid used is generally 0.01 mol to a large excess with respect to 1 mol of compound (16).
  • lithium hydroxide sodium hydroxide, potassium hydroxide etc. are mentioned, for example.
  • the amount of the base to be used is generally 0.01 mol to a large excess, preferably 0.1 to 10 mol, per 1 mol of compound (16).
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 160 ° C.
  • the reaction time is usually 0.5 hour to 48 hours, preferably 1 hour to 15 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, ethylene glycol, water, tetrahydrofuran, 1,4-dioxane, cyclohexane, 1,3-dimethylbenzene, toluene and the like can be mentioned, with preference given to ethylene glycol and water.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • Examples of the combination of two or more of the above reaction solvents include a combination of methanol and water, a combination of ethanol and water, a combination of ethylene glycol and water, and the like, preferably a combination of ethylene glycol and water.
  • Step (13-1) In the step (13-1), the above formula (17) [wherein R 1 , R 2 and B are as defined above, P 1 is a protecting group, and P 2 is a protecting group or a hydrogen atom. Acid azidation reaction of the compound (compound (17)) represented by the above formula (18) [wherein R 1 , R 2 and B are as defined above, P 1 is a protecting group, P 1 2 is a protecting group or a hydrogen atom. ] (Step of obtaining the compound (compound (18))))
  • Examples of the azidation agent to be used include diaryl phosphate azides such as diphenyl phosphate azide.
  • the amount of the azidation agent to be used is generally 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (17).
  • the reaction of the above step (13-1) is preferably carried out in the presence of a base.
  • a base examples include triethylamine, N, N-diisopropylethylamine, N-methylpyrrolidine and the like.
  • the amount of the base to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (17).
  • the reaction temperature is generally 0 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 3 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, 1-propanol, 2 And -propanol, tert-butanol, toluene, benzene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, acetone, methyl ethyl ketone, methylene chloride and chloroform, etc. It is 1,4-dioxane.
  • the above compound (18) is a compound of formula (17) and a halogenated formate (eg, methyl chloroformate) in the presence of the corresponding acid halide (eg, acid chloride, acid bromide, acid iodide, etc.) of compound (17), or a base.
  • a halogenated formate eg, methyl chloroformate
  • Alkali metal azide eg, sodium azide or the like
  • a mixed acid anhydride obtained from ethyl chloroformate, ethyl bromoformate, propyl chloroformate, butyl chloroformate, isobutyl chloroformate, isobutyl bromoformate, hexyl chloroformate, etc.
  • an azidation agent such as potassium azide or the like or trialkylsilyl azide (eg, trimethylsilyl azide, triethylsilyl azide, tri tert-butylsilyl azide or the like).
  • the amount of the azidation agent to be used is generally 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (17).
  • the reaction temperature is generally ⁇ 30 ° C. to 100 ° C., preferably ⁇ 20 ° C. to 30 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 3 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, but, for example, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, N, N-dimethylformamide, N, N-dimethyl form
  • Examples include acetamide, N-methyl-2-pyrrolidone, acetone, methyl ethyl ketone, methylene chloride, chloroform, water and the like, with preference given to acetonitrile, tetrahydrofuran, acetone, methylene chloride, chloroform and water.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • Step (13-2) In the step (13-2), the above formula (18) [wherein R 1 , R 2 and B are as defined above, P 1 is a protecting group, and P 2 is a protecting group or a hydrogen atom.
  • the reaction temperature is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 5 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and includes, for example, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, xylene, water and the like, preferably tetrahydrofuran and 1,4-dioxane It is.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • Step (13-3) In the step (13-3), the above formula (19) [wherein R 1 , R 2 and B are as defined above, P 1 is a protecting group, and P 2 is a protecting group or a hydrogen atom. [Wherein R 1 , R 2 and B are as defined above, P 1 is a protecting group, by allowing a base to act on the compound (compound (19)) represented by the formula] , P 2 is a protecting group or a hydrogen atom. ] (Step of obtaining the compound (compound (20)))))
  • Examples of the base to be used include sodium hydroxide and potassium hydroxide.
  • the amount of the base used is usually 1 mole to a large excess, preferably 1 to 20 moles, per 1 mole of the starting compound (17).
  • the reaction temperature is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 3 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and includes, for example, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, xylene, water and the like, preferably tetrahydrofuran, 1,4-dioxane And water.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • Step (13-4) In the step (13-4), the above formula (20) [wherein R 1 , R 2 and B are as defined above, P 1 is a protecting group, and P 2 is a protecting group or a hydrogen atom.
  • the above formula (21) [wherein R 1 , R 2 and B are as defined above] 1 and P 3 is a protecting group, P 2 is a protecting group or a hydrogen atom.
  • Step of obtaining the compound (compound (21)) is
  • the protective group P 3 of the compound (21) is not particularly limited as long as it has that function, for example, benzyl group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group, 3,4-dimethoxy Aralkyl groups such as benzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and trityl groups; eg formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl Lower alkanoyl groups; arylacyl groups such as benzoyl group and 4-acetoxybenzoyl group; arylalkanoyl groups such as phenylacetyl group; aryloxyalkanoyl groups such as phenoxyacetyl group; such as methoxycarbonyl group and ethoxycarbonyl group; Propyloxycarbo Lower alkoxycarbonyl group such as alkyl group or ter
  • the method for introducing a protective group varies depending on the kind of the protective group and the stability of the compound, but the method described in the literature [Protective Groups in Organic Synthesis, Third Edition, T. W. Green (T.W. Greene), John Wiley & Sons (1999)] or a method according thereto.
  • the method for removing the protecting group varies depending on the type of the protecting group and the stability of the target compound (b-2), but the method described in the literature [Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis) ), 3rd edition, T. W. Solvolysis using, for example, an acid (for example, 0.01 molar to a large excess of acid, preferably trifluoro) according to a method according to Greene (T. W.
  • Acetic acid, formic acid, hydrochloric acid etc. eg solvolysis using a base (eg equimolar to large excess of base, preferably potassium hydroxide or sodium hydroxide etc.); eg hydrogenation metal complex It is carried out by a chemical reduction using an amine or a catalytic reduction using a palladium-carbon catalyst, a Raney nickel catalyst or the like.
  • a base eg equimolar to large excess of base, preferably potassium hydroxide or sodium hydroxide etc.
  • hydrogenation metal complex It is carried out by a chemical reduction using an amine or a catalytic reduction using a palladium-carbon catalyst, a Raney nickel catalyst or the like.
  • Formula (22) [wherein, B is as defined above, and X is a bromine atom, a chlorine atom or an iodine atom.
  • the compound of the formula (compound (22)) is represented by the above formula (3) [wherein, B is as defined above, and X is a bromine atom, a chlorine atom or an iodine atom. ] (Compound (3)) and ammonia can be obtained by the amidation reaction.
  • ammonia to be used examples include 28% ammonia water, ammonia 4% methanol solution, ammonia 4% ethanol solution, ammonia gas and the like.
  • the amount of ammonia to be used is generally 2 mol to a large excess, preferably 2 to 20 mol, per 1 mol of compound (3).
  • the reaction temperature is generally ⁇ 10 ° C. to 40 ° C., preferably ⁇ 10 ° C. to 30 ° C.
  • the reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 1 hour.
  • the reaction solvent is not particularly limited as long as it does not disturb the reaction, and examples thereof include toluene, chloroform, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether, Ethyl acetate, methyl acetate, propyl acetate, acetonitrile and the like can be mentioned, with preference given to tetrahydrofuran.
  • Formula (24) [wherein, B is as defined above, and P 4 is a lower alkyl group.
  • the compound of the formula (compound (24)) is represented by the above formula (22) [wherein, B is as defined above, and X is a bromine atom, a chlorine atom or an iodine atom].
  • Compounds represented by (Compound (22)) in the above formula (23) wherein, P 4 is a lower alkyl group It can obtain by the coupling reaction of the compound (compound (23)) represented by these. More specifically, compound (24) can be obtained by reacting compound (22) with compound (23) in the presence of a base and a palladium catalyst (further optionally, a phosphine ligand).
  • the compound (23) examples include methyl acrylate, ethyl acrylate, propyl acrylate and tert-butyl acrylate.
  • the amount of compound (23) to be used is generally 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of compound (22).
  • Examples of the base to be used include triethylamine, sodium acetate, potassium acetate, sodium hydrogencarbonate, sodium carbonate, cesium fluoride, potassium fluoride, potassium carbonate and potassium phosphate.
  • the amount of the base to be used is generally 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (22).
  • a palladium catalyst to be used for example, tetrakis (triphenylphosphine) palladium (0) (Pd (PPh 3 ) 4 ), palladium (II) acetate (Pd (OAc) 2 ), tris (dibenzylideneacetone) dipalladium (0) And the like. (Pd 2 (dba) 3 ), bis (triphenylphosphine) palladium (II) dichloride ((PPh 3 ) 2 PdCl 2 ), and the like.
  • the amount of palladium catalyst to be used is generally 0.01 to 0.5 mol, preferably 0.05 to 0.2 mol, per 1 mol of compound (22).
  • phosphine ligand for example, triphenylphosphine (PPh 3 ), tris (2-methylphenyl) phosphine (P (o-tol) 3 ), tri (2-furyl) phosphine, tri-tert-butylphosphine (P (tert-Bu) 3 ), 2- [di (tert-butyl) phosphino] -1,1'-biphenyl (JohnPhos), 2- [di (tert-butyl) phosphino] -2'-N, N -Dimethylamino-1,1'-biphenyl (tBuDavePhos), 2- (dicyclohexylphosphino) -1,1'-biphenyl (CyJohnPhos) or 2- (dicyclohexylphosphino) -2'-N, N-dimethylamino- 1,1'-biphenyl (DavePhos
  • the amount of the phosphine ligand to be used is generally 0.01 to 1 mol, preferably 0.05 to 0.5 mol, per 1 mol of compound (22).
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 25 ° C. to 160 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 3 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide, chloroform, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, Acetonitrile, toluene, etc. are mentioned, Preferably it is N, N- dimethylformamide.
  • the compound of the formula (compound (25)) is represented by the above formula (24) [wherein, B is as defined above, and P 4 is a lower alkyl group. ] (Compound (24)) can be obtained by the reductive reaction of. More specifically, a compound (25) can be obtained by reacting a compound (24) having an olefin under a hydrogen atmosphere in the presence of a reduction catalyst such as palladium carbon.
  • Examples of the catalyst used include 5% palladium-activated carbon, 10% palladium-activated carbon, 20% palladium hydroxide-activated carbon, Raney nickel, platinum and platinum oxide.
  • the amount of the catalyst to be used is generally 0.01 to 1 mol, preferably 0.05 to 0.2 mol, per 1 mol of compound (24).
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 20 ° C. to 80 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 18 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include methanol, ethanol, 1-propanol, 2-propanol, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, toluene and the like can be mentioned, with preference given to methanol and ethanol.
  • lithium hydroxide sodium hydroxide, potassium hydroxide etc. are mentioned, for example.
  • the amount of the base to be used is generally 0.01 mol to a large excess with respect to 1 mol of compound (25).
  • the reaction temperature is generally 0 ° C. to 160 ° C., preferably 0 ° C. to 130 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 5 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, water and the like. Is ethanol or water.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • Examples of the combination of two or more of the above reaction solvents include a combination of methanol and water, a combination of ethanol and water, a combination of ethylene glycol and water, and the like, preferably a combination of ethanol and water.
  • Examples of the azidation agent to be used include diaryl phosphate azides such as diphenyl phosphate azide.
  • the amount of the azidation agent to be used is generally 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (26).
  • the reaction of the above step (19-1) is preferably performed in the presence of a base.
  • a base examples include triethylamine, N, N-diisopropylethylamine, N-methylpyrrolidine and the like.
  • the amount of the base to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (26).
  • the reaction temperature is generally 0 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 3 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, 1-propanol, 2 And -propanol, tert-butanol, toluene, benzene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, acetone, methyl ethyl ketone, methylene chloride and chloroform, etc. It is 1,4-dioxane.
  • Compound (27) is a compound (26) and halogenated formate ester (eg methyl chloroformate) in the presence of the corresponding acid halide (eg acid chloride, acid bromide, acid iodide etc.) of compound (26), or a base Alkali metal azide (eg, sodium azide or the like) to a mixed acid anhydride obtained from ethyl chloroformate, ethyl bromoformate, propyl chloroformate, butyl chloroformate, isobutyl chloroformate, isobutyl bromoformate, hexyl chloroformate, etc.) It can also be obtained by reacting an azidation agent such as potassium azide or the like or trialkylsilyl azide (eg, trimethylsilyl azide, triethylsilyl azide, tri tert-butylsilyl azide or the like).
  • an azidation agent such as potassium azide or the like or
  • the amount of the azidation agent to be used is generally 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (26).
  • the reaction temperature is generally ⁇ 30 ° C. to 100 ° C., preferably ⁇ 20 ° C. to 30 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 3 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, but, for example, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, N, N-dimethylformamide, N, N-dimethyl form
  • examples thereof include acetamide, N-methyl-2-pyrrolidone, acetone, methyl ethyl ketone, methylene chloride, chloroform, water and the like, preferably tetrahydrofuran and water.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • the reaction temperature is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 130 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 3 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and includes, for example, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, xylene, water and the like, preferably tetrahydrofuran, 1,4-dioxane and water.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • Examples of the base to be used include sodium hydroxide, potassium hydroxide and ethylenediamine.
  • the amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of the starting compound (26).
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 20 ° C. to 160 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 3 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and includes, for example, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, xylene, water and the like, preferably tetrahydrofuran, 1,4-dioxane and water.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • Grignard reagent examples include methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, ethylmagnesium bromide, ethylmagnesium chloride, propylmagnesium bromide and butylmagnesium chloride.
  • the amount of the Grignard reagent to be used is generally 2 to 10 mol, preferably 3 to 7 mol, per 1 mol of compound (29).
  • the reaction temperature is generally ⁇ 10 ° C. to 80 ° C., preferably 0 ° C. to 60 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 4 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and methyl tert-butyl ether.
  • tetrahydrofuran Preferably tetrahydrofuran.
  • Step (21-1) In the step (21-1), the above formula (30) [wherein, R 1 and R 2 are lower alkyl groups, and X 1 and B are as defined above].
  • the compound of the formula (compound (30)) is reacted with acetonitrile under acidic conditions to give acetonitrile to react with the above formula (31) [wherein R 1 and R 2 are lower alkyl groups, and Me is A methyl group, and X 1 and B are as defined above. ] (Step of obtaining the compound (compound (31)))
  • the amount of acetonitrile used is usually 1 mole to a large excess with respect to 1 mole of compound (30), and can be used as a reaction solvent.
  • the acid used is, for example, concentrated sulfuric acid (and, if necessary, acetic acid).
  • the amount of the acid used is usually 1 mole to a large excess, preferably 1 to 20 moles, per 1 mole of the compound (30).
  • the reaction temperature is generally ⁇ 10 ° C. to 80 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 3 hours.
  • Examples of the base to be used include lithium hydroxide, potassium hydroxide, sodium hydroxide and the like, with preference given to potassium hydroxide.
  • the amount of the base used is usually 1 mole to a large excess with respect to 1 mole of the starting compound (30).
  • the reaction temperature is generally 0 ° C to 170 ° C, preferably 80 ° C to 170 ° C.
  • the reaction time is usually 1 hour to 100 hours, preferably 3 hours to 95 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and includes, for example, methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, ethylene glycol and water, preferably ethylene glycol and water. It is.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • Examples of the combination of two or more of the above reaction solvents include a combination of methanol and water, a combination of ethanol and water, a combination of ethylene glycol and water, and the like, preferably a combination of ethylene glycol and water.
  • B is as defined above, and X is a bromine atom, a chlorine atom or an iodine atom.
  • a cyanide such as zinc cyanide.
  • compound (32) can be obtained by reacting compound (22) with cyanide in the presence of a palladium catalyst (further optionally, a phosphine ligand).
  • Examples of the cyanide to be used include zinc cyanide, sodium cyanide and potassium cyanide.
  • the amount of cyanide to be used is generally 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of compound (22).
  • a palladium catalyst to be used for example, tetrakis (triphenylphosphine) palladium (0) (Pd (PPh 3 ) 4 ), palladium (II) acetate (Pd (OAc) 2 ), bis (dibenzylideneacetone) palladium (0) And the like. (Pd 2 (dba) 3 ), bis (triphenylphosphine) palladium (II) dichloride ((PPh 3 ) 2 PdCl 2 ), and the like.
  • the amount of palladium catalyst to be used is generally 0.01 to 0.5 mol, preferably 0.025 to 0.2 mol, per 1 mol of compound (22).
  • phosphine ligand for example, triphenylphosphine (PPh 3 ), tris (2-methylphenyl) phosphine (P (o-tol) 3 ), tri (2-furyl) phosphine, tri-tert-butylphosphine (P (tert-Bu) 3 ), 2- [di (tert-butyl) phosphino] -1,1'-biphenyl (JohnPhos), 2- [di (tert-butyl) phosphino] -2'-N, N -Dimethylamino-1,1'-biphenyl (tBuDavePhos), 2- (dicyclohexylphosphino) -1,1'-biphenyl (CyJohnPhos), 2- (dicyclohexylphosphino) -2'-N, N-dimethylamino- 1,1'-biphenyl (DavePhos)
  • Ph 3
  • the amount of the phosphine ligand to be used is generally 0.01 to 1 mol, preferably 0.25 to 0.4 mol, per 1 mol of compound (22).
  • a reducing agent such as zinc can be added to the reaction, if necessary.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 25 ° C. to 130 ° C.
  • the reaction time is usually 1 hour to 100 hours, preferably 1 hour to 50 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,4 -Dioxane, acetonitrile, toluene, etc. may be mentioned, preferably N, N-dimethylformamide.
  • the compound of the formula (compound (b-5)) is represented by the above formula (32) [wherein, B is as defined above].
  • Examples of the catalyst to be used include 5% palladium-activated carbon, 10% palladium-activated carbon, 20% palladium hydroxide-activated carbon, Raney nickel, platinum and platinum oxide.
  • the amount of the catalyst to be used is generally 0.01 to 1 mol, preferably 0.05 to 0.2 mol, per 1 mol of compound (32).
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 20 ° C. to 80 ° C.
  • the reaction time is usually 1 hour to 24 hours, preferably 1 hour to 12 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include methanol, ethanol, 1-propanol, 2-propanol, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, Solvents such as 2-methyltetrahydrofuran, 1,4-dioxane and toluene are mentioned, preferably methanol.
  • methyl metal reagent for example, methylboronic acid, trimethylboroxine, potassium methyltrifluoroborate, 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane, tetramethyltin, hexamethylditin And methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, methylzinc bromide, methylzinc chloride and dimethylzinc.
  • the amount of methyl metal reagent to be used is generally 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (5).
  • a palladium catalyst to be used for example, tetrakis (triphenylphosphine) palladium (0) (Pd (PPh 3 ) 4 ), palladium (II) acetate (Pd (OAc) 2 ), bis (dibenzylideneacetone) palladium (0) ) (Pd 2 (dba) 3 ), bis (triphenylphosphine) palladium (II) dichloride ((PPh 3 ) 2 PdCl 2 ) and [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (PdCl 2 (dppf)) and the like.
  • the amount of palladium catalyst to be used is generally 0.01 to 0.5 mol, preferably 0.025 to 0.2 mol, per 1 mol of compound (5).
  • phosphine ligand for example, triphenylphosphine (PPh 3 ), tris (2-methylphenyl) phosphine (P (o-tol) 3 ), tri (2-furyl) phosphine, tri-tert-butylphosphine (P (tert-Bu) 3 ), dicyclohexyl (2 ′, 6′-dimethoxy- [1,1′-biphenyl] -2-yl) phosphine (SPhos), 2- (dicyclohexylphosphino) -2 ′, 4 ', 6'-Triisopropyl-1,1'-biphenyl (XPhos), 1,1'-bis (diphenylphosphino) ferrocene (dppf), 1,1'-bis (di-tert-butylphosphino) ferrocene (Dtbpf) and 2-dicyclohexylphosphino-2
  • the amount of the phosphine ligand to be used is generally 0.01 to 1 mol, preferably 0.25 to 0.4 mol, per 1 mol of compound (5).
  • the reaction of the above scheme 24 is preferably performed in the presence of a base.
  • a base examples include potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate and the like, and for example, potassium carbonate and cesium carbonate are preferable.
  • the amount of the base is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (5).
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 25 ° C. to 120 ° C.
  • the reaction time is usually 1 hour to 48 hours, preferably 1 hour to 6 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide, water, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, 1 And 4-dioxane, toluene and the like, preferably 1,4-dioxane.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • Examples of the combination of two or more of the above reaction solvents include a combination of tetrahydrofuran and water, a combination of 1,2-dimethoxyethane and water, a combination of 1,4-dioxane and water, etc. -A combination of dioxane and water.
  • Formula (33) [wherein, R 1 , R 2 and B are as defined above, P 1 is a protecting group, and P 2 is a protecting group or a hydrogen atom. Wherein R 1 , R 2 and B are as defined above, P 1 is a protecting group, and P 2 is a protecting group or a hydrogen atom, in the above compound (compound (33)) It is. It can obtain by hydrolysis of the cyano group of the compound (compound (16)) represented by these. More specifically, compound (33) can be obtained by hydrolyzing the cyano group of compound (16) in the presence of an acid or a base.
  • Examples of the acid to be used include acetic acid, formic acid, sulfuric acid and hydrochloric acid.
  • the amount of the acid used is generally 0.01 mol to a large excess with respect to 1 mol of compound (16).
  • lithium hydroxide sodium hydroxide, potassium hydroxide etc. are mentioned, for example.
  • the amount of the base to be used is generally 0.01 mol to a large excess, preferably 0.1 to 30 mol, per 1 mol of compound (16).
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 20 ° C. to 130 ° C.
  • the reaction time is usually 0.5 hour to 48 hours, preferably 1 hour to 6 hours.
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, but, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, ethylene glycol, water, dimethyl sulfoxide And 1,4-dioxane etc., preferably 2-propanol, tert-butanol, dimethyl sulfoxide or water.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • the combination of two or more of the above reaction solvents is, for example, a combination of methanol and water, a combination of ethanol and water, a combination of 2-propanol and water, a combination of tert-butanol and water, a combination of dimethyl sulfoxide and water, etc.
  • it is a combination of dimethyl sulfoxide and water.
  • Examples of the acid to be used include sulfuric acid and hydrochloric acid.
  • the amount of the acid used is usually 0.01 mol to a large excess with respect to 1 mol of compound (33).
  • lithium hydroxide sodium hydroxide, potassium hydroxide etc. are mentioned, for example.
  • the amount of the base to be used is generally 0.01 mol to a large excess with respect to 1 mol of compound (33).
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 160 ° C.
  • the reaction time is usually 0.5 hour to 48 hours, preferably 1 hour to 15 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, ethylene glycol, water, 1, Examples thereof include 4-dioxane and the like, preferably methanol, 1-butanol and water.
  • the reaction solvent may be a single solvent or a mixed solvent of two or more in combination.
  • the combination of two or more of the above reaction solvents is, for example, a combination of methanol and water, a combination of ethanol and water, a combination of 2-propanol and water, a combination of 1-butanol and water, a combination of ethylene glycol and water, etc. It can be mentioned.
  • the reaction of the above scheme 26 can also be obtained by reacting a nitrosyl salt (eg, nitrosyl tetrafluoroborate, nitrosyl sulfuric acid, etc.).
  • a nitrosyl salt eg, nitrosyl tetrafluoroborate, nitrosyl sulfuric acid, etc.
  • the amount of the nitrosyl salt to be used is generally 1 to 10 mol, preferably 1 to 6 mol, per 1 mol of compound (33).
  • the reaction temperature is generally 0 ° C. to 100 ° C., preferably 10 ° C. to 30 ° C.
  • the reaction time is usually 0.5 hours to 2 hours, preferably 0.5 hours to 1 hour.
  • the reaction solvent is not particularly limited as long as it does not disturb the reaction, and examples thereof include acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, methylene chloride and the like, preferably N, N-dimethylformamide It is.
  • the compound of the formula (compound (a)) is represented by the above formula (34) [wherein, A is as defined above, and X represents a halogen atom. ]
  • Compound (34) and the compound (compound (35)) represented by said Formula (35) can be obtained by making it react. More specifically, the compound (a) can be obtained by reacting the compound (34) with an anion generated by reacting a compound (35) with a base.
  • the compound (34) may be a commercially available product, and may be produced by appropriately combining known methods or methods described in the examples or methods analogous thereto, as necessary.
  • the compound (35) is a compound known as glycidol. A commercial item can be used.
  • the amount of compound (35) to be used is generally 1 to 10 mol, preferably 1 to 6 mol, per 1 mol of compound (34).
  • the reaction of the above Scheme 27 is preferably performed in the presence of a base.
  • a base for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydride, sodium hydride, potassium hydride, lithium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium hydroxide, lithium hydroxide or sodium hydroxide
  • potassium hydroxide and the like for example, sodium hydride and potassium tert-butoxide are preferable.
  • the amount of the base is generally 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of compound (35).
  • the reaction temperature is usually 0 ° C. to 120 ° C., preferably 5 ° C. to 40 ° C., more preferably 10 ° C. to 30 ° C.
  • the reaction time is usually 0.5 hours to 24 hours, preferably 0.5 hours to 18 hours.
  • the reaction solvent is not particularly limited as long as it has no adverse effect on the reaction, and examples thereof include toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether and the like can be mentioned, and preferably N, N-dimethylformamide.
  • the pharmaceutical composition containing the compound of the formula (I) (hereinafter, also referred to as “the compound of the present invention”), the prophylactic agent, the therapeutic agent and the intraocular pressure lowering agent (hereinafter collectively referred to as “the present invention drug”) are described Do.
  • the present invention pharmaceutical utilizes adrenergic beta 2 receptor antagonist activity and carbonic anhydrase inhibition activity present invention compound has, and performs the prevention or treatment of eye diseases.
  • adrenergic ⁇ 2 receptor antagonist activity refers to the action of the compound of the present invention to suppress the functional expression of the receptor by acting on the adrenergic ⁇ 2 receptor, or the function of the receptor To reduce or eliminate (hereinafter collectively referred to as "suppression of function etc.”). Since the adrenergic ⁇ 2 receptor expressed in the ciliary body of the eye is involved in aqueous humor production, when its function is inhibited etc, the aqueous humor production is suppressed and as a result, the intraocular pressure drops.
  • adrenergic beta 2 receptor antagonist activity includes so-called “beta blocking effect”, “beta receptor blocking activity”, “adrenergic beta 2 receptor inverse agonist activity” and “adrenergic beta 2 receptor partial agonist activity” Etc. are also included.
  • beta blocking action and “beta receptor blocking action” mean that the compound of the present invention inhibits the binding of an adrenergic beta 2 receptor to an agonist (such as adrenaline) to function as a function of the receptor. To suppress and the like.
  • adrenergic beta 2 receptor inverse agonist activity means that the compound of the present invention preferentially has an affinity for "adrenergic beta 2 receptor in an inactivated state", and By stabilizing the active state, it means suppressing the function or the like.
  • adrenergic beta 2 receptor partial agonist activity refers to agonist activity that is weaker than full agonist (such as adrenaline). It is known that weakly active partial agonists act as antagonists for receptors in the activated state in the presence of a full agonist. Therefore, the “adrenergic ⁇ 2 receptor partial agonist” acts in the direction of inhibiting the activation of the adrenergic ⁇ 2 receptor by a full agonist (such as adrenalin), and as a result, the function of the receptor is suppressed or the like.
  • the present compounds are, in addition to adrenergic beta 2 receptor antagonist activity may have antagonist activity against other adrenoceptor subtypes (e.g. adrenergic beta 1 receptor).
  • adrenergic beta 2 receptor antagonist activity may have antagonist activity against other adrenoceptor subtypes (e.g. adrenergic beta 1 receptor).
  • carbonic anhydrase inhibitory activity refers to the fact that the compound of the present invention inhibits the function of carbonic anhydrase to eliminate or attenuate its activity. Since carbonic anhydrase is involved in aqueous humor production, loss or attenuation of its activity suppresses aqueous humor production, resulting in a drop in intraocular pressure.
  • carbonic anhydrase exists in nature as many different isoforms.
  • Examples of such carbonic anhydrase isozymes include carbonic anhydrase I (CA-I), carbonic anhydrase II (CA-II), carbonic anhydrase III (CA-III), carbonic anhydrase IV (CA-IV) ), Carbonic anhydrase VA (CA-VA), carbonic anhydrase VB (CA-VB), carbonic anhydrase VI (CA-VI), carbonic anhydrase VII (CA-VII), carbonic anhydrase VIII (CA-VIII) ), Carbonic anhydrase IX (CA-IX), carbonic anhydrase X (CA-X), carbonic anhydrase XI (CA-XI), carbonic anhydrase XII (CA-XII), carbonic anhydrase XIII (CA-XIII) ), Carbonic anhydrase XIV (CA
  • carbonic anhydrase II (CA-II) is a preferred target carbonic anhydrase isozyme of the compounds of the present invention.
  • the compounds of the present invention can eliminate or attenuate their activity by inhibiting carbonic anhydrase II (CA-II).
  • the compound of the present invention may have an inhibitory activity against other isozymes of carbonic anhydrase.
  • the compound of the present invention (the pharmaceutical agent of the present invention) is characterized in that either or both of the adrenergic beta 2 receptor and the carbonic anhydrase are active based on having both adrenaline beta 2 receptor antagonist activity and carbonic anhydrase inhibitory activity. It can be used for the treatment or prevention of a disease involved.
  • Examples of diseases in which the adrenergic ⁇ 2 receptor is involved include (1) eye diseases (glaucoma, hypertonia and the like), (2) chronic obstructive pulmonary disease (COPD) and (3) infantile hemangiomas and the like.
  • eye diseases glaucoma, hypertonia and the like
  • COPD chronic obstructive pulmonary disease
  • infantile hemangiomas examples include (1) eye diseases (glaucoma, hypertonia and the like), (2) chronic obstructive pulmonary disease (COPD) and (3) infantile hemangiomas and the like.
  • the diseases involving carbonic anhydrase include, for example, (1) eye diseases (glaucoma, hypertonia etc.), (2) epilepsy, (3) respiratory acidosis, (4) cardiac edema, (5) hepatic edema, (6) premenstrual tension, (7) meniere's disease and Meniere's syndrome, and (8) sleep apnea syndrome etc. are mentioned.
  • the eye disease is a disease involving both an adrenergic ⁇ 2 receptor and carbonic anhydrase. Therefore, the compound of the present invention (the medicament of the present invention) is particularly useful for the treatment or prevention of eye diseases.
  • Eye diseases include glaucoma (primary open angle glaucoma, normal tension glaucoma, primary closed angle glaucoma, plateau iris glaucoma, secondary open angle glaucoma, secondary closed angle glaucoma, developmental glaucoma, etc.)
  • Intraocular hypertension, macular edema, macular degeneration, elevation of retina and optic nerve tension, myopia, hyperopia, astigmatism, dry eye, retinal detachment, cataract, trauma or inflammation etc. increase in intraocular pressure, increase in intraocular pressure by drugs such as steroids or hormones, It includes, but is not limited to, postoperative intraocular pressure increase and the like.
  • the compounds of the present invention can reduce intraocular pressure based on having both an adrenergic beta 2 receptor antagonist activity and a carbonic anhydrase inhibitory activity. Therefore, the compound of the present invention (the pharmaceutical agent of the present invention) is a disease having a large influence of intraocular pressure, specifically, glaucoma, hypertonia, elevated intraocular pressure due to trauma, elevated intraocular pressure due to inflammation, elevated intraocular pressure due to drugs and surgery It is particularly useful for the prevention and treatment of the subsequent rise in intraocular pressure.
  • the compounds of the present invention can be used in combination with other drugs (hereinafter also referred to as “combination drugs").
  • combination means that a plurality of medicines are used in combination as an active ingredient.
  • use as a combination drug, use as a kit, use in combination characterized in that each is separately administered by the same or different administration route, and the like can be mentioned.
  • the administration time of the concomitant drug is not limited, and the compound of the present invention may be administered simultaneously with the administration subject, or may be administered with a time lag.
  • the dose of the concomitant drug may be determined according to the dose clinically used, and may be appropriately selected depending on the administration subject, the age and body weight of the administration subject, symptoms, administration time, dosage form, administration method, combination, etc. it can.
  • the administration mode of the concomitant drug is not particularly limited, as long as the compound of the present invention (the present invention drug) and the concomitant drug are combined at the time of administration.
  • concomitant drugs for example, “sympathomimetics”, “sympathomimetics”, “parasympathomimetics”, “prostaglandin related drugs”, “carbonic anhydrase” Inhibitors, “Rho kinase (ROCK) inhibitors”, “hypertonic osmotic agents” and the like can be mentioned.
  • sympathomimetics for example, “sympathomimetics”, “sympathomimetics”, “parasympathomimetics”, “prostaglandin related drugs”, “carbonic anhydrase” Inhibitors, “Rho kinase (ROCK) inhibitors”, “hypertonic osmotic agents” and the like can be mentioned.
  • ROCK Rho kinase
  • sympathomimetic agents include adrenergic alpha 2 receptor stimulants such as apraclonidine hydrochloride and brimonidine tartrate; and adrenalin beta 2 receptor stimulants such as dipivephrine hydrochloride and the like.
  • sympatholytic agents examples include adrenergic alpha 1 receptor blockers such as bunazosin hydrochloride; adrenergic beta 2 receptor antagonists such as timolol maleate and carteolol hydrochloride; adrenaline such as betaxolol hydrochloride ⁇ 1 receptor antagonists; ⁇ receptor blockers such as levobnolol and nipladilol.
  • adrenergic alpha 1 receptor blockers such as bunazosin hydrochloride
  • adrenergic beta 2 receptor antagonists such as timolol maleate and carteolol hydrochloride
  • adrenaline such as betaxolol hydrochloride ⁇ 1 receptor antagonists
  • ⁇ receptor blockers such as levobnolol and nipladilol.
  • parasympathetic nerve stimulant examples include pilocarpine hydrochloride, carbachol, deme potassium bromide, ecothiophate, distigmine bromide and the like.
  • prostaglandin related drug examples include prost drugs such as latanoprost, tafluprost and travoprost; for example, prostamide drugs such as bimatoprost; for example, prostone drugs such as isopropyl unoprostone;
  • prost drugs such as latanoprost, tafluprost and travoprost
  • prostamide drugs such as bimatoprost
  • prostone drugs such as isopropyl unoprostone
  • EP2 agonists such as denepag isopropyl
  • EP3 agonists etc . for example, FP ⁇ EP3 dual agonists such as sepetaprost; for example, EP4 agonists etc.
  • carbonic anhydrase inhibitor examples include dorzolamide hydrochloride, brinzolamide, acetazolamide, diclofenamide, methazolamide and the like.
  • Rho kinase (ROCK) inhibitors examples include ripasdil hydrochloride, fasudil hydrochloride, Y-27632 ([((R)-(+)-trans-N- (4-pyridyl) -4- (1 -Aminoethyl) -cyclohexanecarboxamide dihydrochloride monohydrate]), Y-39983 (SNJ-1656) (4-[(1R) -1-aminoethyl] -N- (1H-pyrrolo [2,3-] b) pyridin-4-yl) benzamide dihydrochloride), AR-13324, AMA0076, H-1129 and the like.
  • hypothermic osmotic agent examples include combination preparations of glycerin, glycerin and fructose, isosorbide, D-mannitol and the like.
  • Both the compound of the present invention and the pharmaceutical of the present invention can be provided as a preparation.
  • Formulation includes oral and parenteral formulations.
  • oral preparations include tablets, capsules, powders and granules.
  • Parenteral preparations include, for example, sterile liquid preparations such as solutions or suspensions, specifically eye drops, eye ointments, injections and drops.
  • the formulations according to the invention may usually comprise a therapeutically effective amount of a compound of the invention together with a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically acceptable carrier or diluent for oral or parenteral preparation (eg, eye drops, eye ointments, etc.) in a number of ways familiar to those skilled in the art can do.
  • excipients eg, fat, beeswax, semi-solid and liquid polyols, natural or hardened oils, etc.
  • water eg, distilled water, in particular, distilled for injection
  • alcohol eg ethanol
  • glycerol polyol, glucose aqueous solution, mannitol, vegetable oil etc .
  • additives eg, bulking agent, disintegrant, binder, lubricant, wetting agent, stable
  • the formulation according to the present invention can be selected in various forms.
  • oral preparations such as tablets, capsules, powders, granules or solutions
  • sterile liquid parenteral preparations such as solutions or suspensions, suppositories, ointments and the like can be mentioned.
  • the preparation according to the present invention may be a solid preparation or a liquid preparation.
  • the solid preparation can be produced as it is in the form of a tablet, capsule, granule or powder, but can also be produced using a suitable carrier (additive).
  • suitable carriers for example, saccharides such as lactose or glucose; starches such as corn, wheat or rice; fatty acids such as stearic acid; inorganic salts such as magnesium aluminometasilicate or anhydrous calcium phosphate etc.
  • Synthetic polymers such as polyvinyl pyrrolidone or polyalkylene glycol; fatty acid salts such as calcium stearate or magnesium stearate; alcohols such as stearyl alcohol or benzyl alcohol; such as methyl cellulose, carboxymethyl cellulose, ethyl cellulose or hydroxypropyl methyl cellulose
  • Synthetic cellulose derivatives and other commonly used additives such as gelatin, talc, vegetable oil, gum arabic and the like can be mentioned.
  • solid preparations such as tablets, capsules, granules and powders are generally, for example, 0.1 to 100% by mass, preferably the compound represented by the above formula (I), based on the mass of the whole preparation, preferably May contain 5 to 98% by mass as an active ingredient.
  • the liquid preparation uses water, alcohols and appropriate additives usually used in liquid preparations, and is in the form of suspension, syrup, injection, drip infusion (intravenous infusion), eye drops, eye ointment, etc. Manufactured.
  • Suitable solvents or diluents for parenteral administration in the form of intramuscular injection, intravenous injection or subcutaneous injection include, for example, distilled water for injection, lidocaine hydrochloride aqueous solution (for intramuscular injection), physiological saline, An aqueous solution of glucose, ethanol, polyethylene glycol, propylene glycol, a liquid for intravenous injection (for example, an aqueous solution such as citric acid and sodium citrate), an electrolyte solution (for intravenous drip and intravenous injection) and the like can be mentioned. These solvents or diluents can be used as a mixed solution thereof.
  • injections may take the form of dissolving the active ingredient in advance or dissolving the active ingredient as powder or to which a suitable carrier (additive) is added at the time of use.
  • a suitable carrier additive
  • These injection solutions can contain, for example, 0.1 to 10% by weight of an active ingredient based on the weight of the entire preparation.
  • suspensions for oral administration and solutions such as syrups can each contain, for example, 0.1 to 10% by mass of an active ingredient based on the mass of the whole preparation.
  • the formulation of the present invention can suitably be administered as eye drops.
  • Additives commonly used in eye drops are, for example, solubilizers such as polyoxyethylene hydrogenated castor oil, polyoxyl 40 stearic acid, polyvinyl pyrrolidone and polysorbate 80; and stabilizers such as sodium edetate, polyvinyl pyrrolidone and polysorbate 80, etc.
  • solubilizers such as polyoxyethylene hydrogenated castor oil, polyoxyl 40 stearic acid, polyvinyl pyrrolidone and polysorbate 80
  • stabilizers such as sodium edetate, polyvinyl pyrrolidone and polysorbate 80, etc.
  • potassium chloride, sodium chloride, concentrated glycerin, tonicity agent such as glucose or D-mannitol
  • sodium citrate, sodium acetate, sodium hydrogen carbonate, trometamol, boric acid, borax, sodium hydrogen phosphate or phosphoric acid Buffers such as sodium dihydrogen
  • pH adjusters such as hydrochloric acid and sodium hydroxide
  • preservatives such as benzalkonium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol and sorbic acid (preservative);
  • carboxyvinyl polymers, polyvinyl pyrrolidone with polyvinyl alcohol, hydroxyethyl cellulose, hypromellose, additives conventionally used may be mentioned as ophthalmic preparation of thickening agents such as methylcellulose and glycerin.
  • the pH of the eye drop may be in the range which is acceptable as an ophthalmic preparation.
  • the range of pH of the eye drop is preferably 4 to 8.
  • the osmotic pressure ratio of the eye drop to the saline may be within an acceptable range for an ophthalmic preparation.
  • the osmotic pressure ratio of the eye drop to the saline is preferably in the range of 0 to 4, more preferably in the range of 0 to 2, and most preferably around 1.
  • the preparation of the present invention can also be administered as an eye ointment.
  • a base usually used as an ophthalmic preparation such as white petrolatum and liquid paraffin can be used.
  • the concentration of the compound of the present invention in the eye drop and eye ointment is not particularly limited, but is, for example, 0.00001 to 5 w / v%, preferably 0.0001 to 2 w / v%, based on the volume of the whole eye drop. More preferably, it can contain 0.001 to 1 w / v% of the active ingredient.
  • the concentration of the compound of the present invention in the eye drop may be calculated based on the weight of any of the free form of the compound and the salt thereof.
  • the number of times of administration of the eye drop and the eye ointment can be set appropriately, and may be, for example, once to several times a day.
  • CHROMATOREX (Registered trademark) Q-PACK SI, CHROMATOREX (registered trademark) Q-PACK NH manufactured by Fuji Silysia Chemical, or CHROMATOREX (registered trademark) Q-PACK CO 2 H manufactured by Fuji Silysia Chemical, using ethyl acetate-hexane as a mobile phase , Methanol-chloroform or methanol-ethyl acetate was used.
  • Reverse phase silica gel column chromatography Biotage® SNAP Ultra C18 Cartridge is used as a column, 0.1% aqueous solution of trifluoroacetic acid and 0.1% solution of acetonitrile in acetonitrile as a mobile phase was used.
  • 1 H-NMR was measured using AL400 or ECZ400S (400 MHz) manufactured by JEOL Ltd.
  • tetramethylsilane is used as an internal standard when measuring with a heavy chloroform solution
  • methanol is used as an internal standard when measuring with a heavy methanol solution
  • water is used as an internal standard when measuring with a heavy aqueous solution. It was.
  • ESI electrospray ionization
  • Waters ACQUITY® SQD The microwave reaction was performed using Biotage's Initiator (registered trademark).
  • Trimethylboroxine (0.38 mL, 2.7 mmol)
  • Pd Pd (PPh 3 ) in a solution of commercially available 3-bromo-5-hydroxybenzoic acid (297 mg, 1.4 mmol) in 1,2-dimethoxyethane (2.5 mL) ) 4 (158 mg, 0.14 mmol) and 2N aqueous solution of sodium carbonate (2.1 mL, 4.1 mmol) were added at room temperature, and stirred under argon atmosphere at 90 ° C. for 2 hours using a microwave reactor. To the reaction mixture was added 5N hydrochloric acid, and the mixture was extracted with ethyl acetate.
  • Zinc cyanide (63 mg, 0.53 mmol), XPhos (26 mg, 0.053 mmol) and Pd 2 (dba) 3 (24 mg, 0.027 mmol) were added to the reaction mixture at room temperature, and the microwave reactor was operated under an argon atmosphere.
  • Ammonium chloride (841 mg, 16 mmol), sodium cyanide (704 mg, 14 mmol) and 28% aqueous ammonia (14 mL) were added to a THF (14 mL) -water (43 mL) mixed solution at room temperature and cooled to 0 ° C.
  • Commercially available cyclopropanecarboxaldehyde (1.0 g, 14 mmol) was added to the reaction mixture at 0 ° C. and stirred at room temperature for 24 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered.
  • Lithium aluminum hydride (75 mg, 2.0 mmol) was added at room temperature to a solution of commercially available 2-fluoro-4-methylbenzoic acid (102 mg, 0.66 mmol) in THF (3.3 mL) at 70 ° C. under an argon atmosphere. The mixture was stirred for 1 hour. The reaction mixture was cooled to 0 ° C., methanol and saturated aqueous potassium sodium tartrate solution were added, and stirred at room temperature for 1 hour. The reaction mixture was filtered, water was added to the filtrate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • Phosphorous tribromide (0.068 mL, 0. 2) was added to a mixed solution of commercially available 4-hydroxy-2- (trifluoromethyl) pyridine (97 mg, 0.60 mmol) in dichloromethane (1.2 mL) -DMF (1.2 mL). 72 mmol was added at room temperature and stirred at 80 ° C. for 1 hour. The reaction mixture was purified by silica gel column chromatography to give a colorless oil (84 mg).

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Abstract

La présente invention concerne un composé ayant une activité antagoniste du récepteur β2-adrénergique et une activité inhibitrice d'anhydrase carbonique, et qui présente une excellente activité d'hypertension oculaire. L'invention concerne en particulier un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. (Dans la formule, A représente un groupe phényle éventuellement substitué, etc. ; R1 et R2 représentent chacun indépendamment un atome d'hydrogène, etc. X1 représente une liaison simple, etc. X2 représente une liaison simple, etc. B représente une formule générale : formule (AA) ou formule (BB) (W1 étant un atome d'azote, etc. ; W2 étant un atome d'oxygène, etc. ; W3 étant un atome d'azote, etc. ; Rb1 étant un groupe phényle éventuellement substitué, etc. ; Rb2 étant un atome d'hydrogène, etc.)]
PCT/JP2018/048284 2017-12-27 2018-12-27 Composé aryloxy WO2019131922A1 (fr)

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CN110627714A (zh) * 2019-10-16 2019-12-31 安庆博曼生物技术有限公司 3-氟-2-三氟甲基异烟酸的合成方法
CN112920138A (zh) * 2021-01-27 2021-06-08 成都摩尔生物医药有限公司 一种噻吗洛尔杂质的制备方法

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WO2002006274A1 (fr) * 2000-07-17 2002-01-24 Wyeth N-(4-sulfonylaryl)cyclylamine-2-hydroxyethylamines: agonistes du recepteur beta-3 adrenergique
WO2002048134A2 (fr) * 2000-12-11 2002-06-20 Bayer Pharmaceuticals Corporation Agonistes adrenorecepteurs beta-3 de derives chroman aminomethyl bi-substitues
WO2012086727A1 (fr) * 2010-12-22 2012-06-28 株式会社デ・ウエスタン・セラピテクス研究所 Nouveau dérivé d'isoquinoléine substitué

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WO2002006229A2 (fr) * 2000-07-17 2002-01-24 Wyeth Agonistes des beta-3 recepteurs adrenergiques heterocycliques
WO2002006274A1 (fr) * 2000-07-17 2002-01-24 Wyeth N-(4-sulfonylaryl)cyclylamine-2-hydroxyethylamines: agonistes du recepteur beta-3 adrenergique
WO2002048134A2 (fr) * 2000-12-11 2002-06-20 Bayer Pharmaceuticals Corporation Agonistes adrenorecepteurs beta-3 de derives chroman aminomethyl bi-substitues
WO2012086727A1 (fr) * 2010-12-22 2012-06-28 株式会社デ・ウエスタン・セラピテクス研究所 Nouveau dérivé d'isoquinoléine substitué

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110627714A (zh) * 2019-10-16 2019-12-31 安庆博曼生物技术有限公司 3-氟-2-三氟甲基异烟酸的合成方法
CN112920138A (zh) * 2021-01-27 2021-06-08 成都摩尔生物医药有限公司 一种噻吗洛尔杂质的制备方法
CN112920138B (zh) * 2021-01-27 2023-03-07 成都摩尔生物医药有限公司 一种噻吗洛尔杂质的制备方法

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